Kinase Inhibitors

ABSTRACT

The present invention provides kinase inhibitors of Formula I:

BACKGROUND OF THE INVENTION

The p38 kinase is a mitogen-activated protein (MAP) kinase that belongsto the serine/threonine kinase superfamily. This kinase is activated byextracellular stresses such as heat, UV light, and osmotic stress, aswell as by inflammatory stimuli such as lipopolysaccharide. Whenactivated, p38 kinase phosphorylates intracellular protein substratesthat regulate the biosynthesis of the pro-inflammatory cytokines tumornecrosis factor α (TNF-α) and interleukin-β (IL-1β). These cytokines areimplicated in the pathology of a number of chronic inflammatorydisorders (Lee, et al., Ann. N.Y. Acad. Sci., 696, 149-170 (1993);Muller-Ladner, Curr. Opin. Rheumatol., 8, 210-220 (1996)),cardiovascular and central nervous system disorders (Salituro, et al.,Current Medicinal Chemistry, 6, 807-823 (1999)), and autoimmunedisorders (Pargellis, et al., Nature Structural Biology, 9(4), 268-272(2002)).

A number of urea compounds (for example, WO 9923091, WO 01012188, WO04004720, WO 04037789, WO 99/32111, US 2004/0058961, WO 2004/100946, andWO 0043384) have been identified as p38 kinase inhibitors or cytokineinhibitors. However, there remains a need for treatment in this fieldfor compounds that are cytokine suppressive drugs, i.e., compounds thatare capable of inhibiting p38 kinase.

The present invention provides new inhibitors of p38 kinase useful forthe treatment of conditions resulting from excessive cytokineproduction.

BRIEF SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I:

wherein:

R¹ is hydrogen, C₁-C₄ alkyl, or tolyl;

W is 1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C₁-C₂ alkoxy)-naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,(1-Y-piperidin-4-yloxy)-phenyl-,[1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-,(1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenylis optionally substituted with one to two substituents from the groupconsisting of halo, methyl, and trifluoromethyl;

Y is —C(O)—R², C₁-C₃ alkylsulfonyl, or cyclopropylsulfonyl; and

R² is C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy-(C₁-C₆ alkyl), amino,benzyloxy, indolyl, tetrahydrofuryl, piperidinyl, trichloromethyl,cyclopentylmethyl; C₃-C₅ cycloalkyl optionally substituted with 1-3substituents independently selected from the group consisting of phenyl,C₁-C₄ alkyl, and halo, pyridinyl optionally substituted with 1-2substituents independently selected from the group consisting of C₁-C₄alkoxy and halo, thienyl optionally substituted with 1-2 halo or C₁-C₄alkyl substituents, pyrrolyl optionally substituted with 1-2 C₁-C₄ alkylsubstituents, imidazolyl, pyrazolyl optionally substituted with 1-3C₁-C₄ alkyl substituents, or phenyl optionally substituted with 1-2substituents independently selected from the group consisting of halo,trifluoromethyl, trifluoromethoxy, C₁-C₄ alkoxy,4-methylpiperazin-1-ylmethyl, 2-(dimethylamino)ethoxy, andmorpholin-4-ylmethyl;

or a pharmaceutically acceptable salt thereof.

The present invention provides a method of inhibiting p-38 kinase in amammal comprising administering to a mammal in need of such treatment aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a method of suppressing theproduction of tumor necrosis factor α (TNF-α) in a mammal comprisingadministering to a mammal in need of such treatment an effective amountof a compound of Formula I or a pharmaceutically acceptable saltthereof.

The present invention also provides a method of suppressing theproduction of interleukin-β (IL-1β) in a mammal comprising administeringto a mammal in need of such treatment an effective amount of a compoundof Formula I or a pharmaceutically acceptable salt thereof.

The present invention further provides a method of treating conditionsresulting from excessive cytokine production in a mammal comprisingadministering to a mammal in need of such treatment acytokine-suppressing amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

The present invention also provides a method of inhibiting the growth ofa susceptible neoplasm in a mammal comprising administering to a mammalin need of such treatment a p38 inhibiting amount of a compound ofFormula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method of inhibiting metastasis ina mammal comprising administering to a mammal in need of such treatmenta p38 inhibiting amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a method of treating rheumatoidarthritis in a mammal comprising administering to a mammal in need ofsuch treatment a p38 inhibiting amount of a compound of Formula I or apharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical formulationcomprising a compound of Formula I or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable excipient,carrier, or diluent.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the inhibition of p38 kinase. Additionally, thisinvention provides a compound of Formula I or a pharmaceuticallyacceptable salt thereof for use in the inhibition of p38 kinase inmammals. Furthermore, this invention provides a pharmaceuticalcomposition adapted for the inhibition of p38 kinase comprising acompound of Formula I or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable excipients,carriers, or diluents thereof.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the suppression of the production of tumor necrosisfactor α (TNF-α). Additionally, this invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof for use in thesuppression of the production of tumor necrosis factor α (TNF-α) inmammals. Furthermore, this invention provides a pharmaceuticalcomposition adapted for the suppression of the production of tumornecrosis factor α (TNF-α) comprising a compound of Formula I or apharmaceutically acceptable salt thereof in combination with one or morepharmaceutically acceptable excipients, carriers, or diluents.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the suppression of the production of interleukin-1β(IL-1β). Additionally, this invention provides a compound of Formula Ior a pharmaceutically acceptable salt thereof for use in the suppressionof the production of interleukin-1β (IL-1β) in mammals. Furthermore,this invention provides a pharmaceutical composition adapted for thesuppression of the production of interleukin-1β (IL-1β) comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof, incombination with one or more pharmaceutically acceptable excipients,carriers, or diluents.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of conditions resulting from excessivecytokine production. Additionally, this invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof for use in thetreatment of conditions resulting from excessive cytokine production inmammals. Furthermore, this invention provides a pharmaceuticalcomposition adapted for the treatment of conditions resulting fromexcessive cytokine production comprising a compound of Formula I or apharmaceutically acceptable salt thereof in combination with one or morepharmaceutically acceptable excipients, carriers, or diluents.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the inhibition of growth of a susceptible neoplasm.Additionally, this invention provides a compound of Formula I or apharmaceutically acceptable salt thereof for use in the inhibition ofgrowth of a susceptible neoplasm in mammals. Furthermore, this inventionprovides a pharmaceutical composition adapted for the inhibition ofgrowth of a susceptible neoplasm comprising a compound of Formula I or apharmaceutically acceptable salt thereof in combination with one or morepharmaceutically acceptable excipients, carriers, or diluents.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the inhibition of metastasis. Additionally, thisinvention provides a compound of Formula I or a pharmaceuticallyacceptable salt thereof for use in the inhibition of metastasis inmammals. Furthermore, this invention provides a pharmaceuticalcomposition adapted for the inhibition of metastasis comprising acompound of Formula I or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable excipients,carriers, or diluents.

This invention also provides the use of a compound of Formula I or apharmaceutically acceptable salt thereof for the manufacture of amedicament for the treatment of rheumatoid arthritis. Additionally, thisinvention provides a compound of Formula I or a pharmaceuticallyacceptable salt thereof for use in the treatment of rheumatoid arthritisin mammals. Furthermore, this invention provides a pharmaceuticalcomposition adapted for the treatment of rheumatoid arthritis comprisinga compound of Formula I or a pharmaceutically acceptable salt thereof incombination with one or more pharmaceutically acceptable excipients,carriers, or diluents.

DETAILED DESCRIPTION OF THE INVENTION

The general chemical terms used in the formulae above have their usualmeanings.

For example, the term “C₁-C₆ alkyl” includes straight chain and branchedalkyls, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, and hexyl moieties. The term “C₁-C₄alkyl” is included within the meaning of the term “C₁-C₆ alkyl” andincludes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,and tert-butyl. The term “C₁-C₆ alkoxy” includes methoxy, ethoxy,propoxy, butoxy, pentoxy, and hexoxy. The term “C₁-C₄ alkoxy” includesmethoxy, ethoxy, propoxy, and butoxy. The term “C₁-C₆ alkoxy-(C₁-C₆alkyl)” refers to an alkoxy group attached through an alkylene linker.The term “C₁-C₃ alkylsulfonyl” refers to a sulfonyl group that issubstituted with a methyl, ethyl, or propyl group. The term “C₃-C₅cycloalkyl” includes cyclopropyl, cyclobutyl, and cyclopentyl moieties.The term “halo” includes fluoro, chloro, bromo, and iodo.

The term “p-38 kinase” is taken to mean the p-38a and/or p-38α kinaseisoforms.

The term “suppressing the production of TNF-α (IL-1β, cytokine)” istaken to mean decreasing of excessive in vivo levels of TNF-α, IL-1β, oranother cytokine in a mammal to normal or sub-normal levels. This may beaccomplished by inhibition of the in vivo release of TNF-α, IL-1β, oranother cytokine by all cells, including macrophages; by downregulation, at the genomic level, of excessive in vivo levels of TNF-α,IL-1β, or another cytokine in a mammal to normal or sub-normal levels;by inhibition of the synthesis of TNF-α, IL-1β, or another cytokine as aposttranslational event; or by a down regulation of TNF-α, IL-1β, oranother cytokine at the translational level.

The skilled artisan will appreciate that certain compounds of Formula Icontain at least one chiral center. The present invention contemplatesall individual enantiomers or diastereomers, as well as mixtures of theenantiomers and diastereomers of said compounds including racemates. Itis preferred that compounds of Formula I containing at least one chiralcenter exist as single enantiomers or diastereomers. The singleenantiomers or diastereomers may be prepared beginning with chiralreagents or by stereoselective or stereospecific synthetic techniques.Alternatively, the single enantiomers or diastereomers may be isolatedfrom mixtures by standard chiral chromatographic or crystallizationtechniques.

It will be understood by the skilled reader that most or all of thecompounds of the present invention are capable of forming salts. In allcases, the pharmaceutically acceptable salts of all of the compounds areincluded in the names of them. The compounds of the present inventionare amines, and accordingly react with any of a number of inorganic andorganic acids to form pharmaceutically acceptable acid addition salts.Preferred pharmaceutically acceptable salts are those formed withhydrochloric acid and methanesulfonic acid.

While all of the compounds of Formula I are useful inhibitors of p-38kinase, certain classes of compounds are preferred. The followingparagraphs describe such preferred classes:

-   -   a) W is [1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,        (1-Y-piperazin-4-yl)-phenyl-, or (1-Y-piperidin-4-yloxy)-phenyl-    -   b) Y is C(O)—R²;    -   c) R¹ is methyl;    -   d) R¹ is tolyl;    -   e) R² is phenyl substituted 1-2 times with halo;    -   f) R² is tert-butyl;    -   g) R² is cyclopropyl;

Preferred embodiments of the present invention include all combinationsof paragraphs a)-g).

The compounds of Formula I are inhibitors of p38 kinase. Thus, thepresent invention also provides a method of inhibiting p38 kinase in amammal that comprises administering to a mammal in need of saidtreatment a p38 kinase-inhibiting amount of a compound of Formula I. Itis preferred that the mammal to be treated by the administration of thecompounds of Formula I is human.

As inhibitors of p38 kinase, the compounds of the present invention areuseful for suppressing the production of the pro-inflammatory cytokinestumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), andtherefore for the treatment of disorders resulting from excessivecytokine production. The present compounds are therefore believed to beuseful in treating inflammatory disorders, including eczema, atopicdermatitis, rheumatoid arthritis, osteoarthritis, inflammatory boweldisease, and toxic shock syndrome. The compounds of the presentinvention are also believed to be useful in the treatment ofcardiovascular disorders, such as acute myocardial infarction, chronicheart failure, atherosclerosis, viral myocarditis, cardiac allograftrejection, and sepsis-associated cardiac dysfunction. Furthermore, thecompounds of the present invention are also believed to be useful forthe treatment of central nervous system disorders, such as meningococcalmeningitis, Alzheimer's disease, Parkinson's disease, and multiplesclerosis.

Most solid tumors increase in mass through the proliferation ofmalignant cells and stromal cells, including endothelial cells. In orderfor a tumor to grow larger than 2-3 millimeters in diameter, it mustform a vasculature, a process known as angiogenesis.

Suppression of tumor-induced angiogenesis by angiostatin and endostatinhas been reported to result in antitumor activity (O'Reilly, et al.,Cell, 88, 277-285 (1997)). The selective p38 kinase inhibitor SB22025has been shown to inhibit angiogenesis (J. R. Jackson, et al., J.Pharmacol. Exp. Therapeutics, 284, 687 (1998)). Because angiogenesis isa critical component of the mass expansion of most solid tumors, thedevelopment of new p38 kinase inhibitors for the inhibition of thisprocess represents a promising approach for antitumor therapy. Thisapproach to antitumor therapy may lack the toxic side effects or drugresistance-inducing properties of conventional chemotherapy (JudahFolkman, Endogenous Inhibitors of Angiogenesis, The Harvey Lectures,Series 92, pages 65-82, Wiley-Liss Inc., (1998)).

As inhibitors of p38 kinase, the compounds of the present invention,therefore, are also useful in inhibiting growth of susceptibleneoplasms. Schultz, R. M. Potential of p38 MAP kinase inhibitors in thetreatment of cancer. In: E. Jucker (ed.), Progress in Drug Research, 60,59-92, (2003). A susceptible neoplasm is defined to be a neoplasm thatdepends upon p38 kinase for its survival, growth, or metastasis.Susceptible neoplasms include tumors of the brain, genitourinary tract,lymphatic system, stomach, larynx, and lung (U.S. Pat. No. 5,717,100).Preferably, the term “susceptible neoplasms” as used in the presentapplication includes human cancers including non-small cell lungcarcinoma (A. Greenberg, et al., Am. J. Respir. Cell Mol. Biol., 26, 558(2002)), breast carcinoma (J. Chen, et al., J. Biol. Chem., 276, 47901(2001); B. Salh, et al., Int. J. Cancer, 98, 148 (2002); and S. Xiong,et al., Cancer Res., 61, 1727 (2001)), gastric carcinoma (Y. D. Jung, etal., Proc. Am. Assoc. Cancer Res., 43, 9 (2002)), colorectal carcinomas(S. Xiong, et al., Cancer Res., 61, 1727 (2001)), and malignant melanoma(C. Denkert, et al., Clin. Exp. Metastasis, 19, 79 (2002)).

Inhibition of angiogenesis by suppression of TNF-α has also been taughtto be useful in the inhibition or prevention of metastasis (U.S. Pat.No. 6,414,150; U.S. Pat. No. 6,335,336). Furthermore, suppression ofTNF-α is indicated for the treatment and prevention of cachexia, awasting syndrome experienced by about half of all cancer patients (T.Yoneda, et al., J. Clin. Invest., 87, 977 (1991)).

Furthermore, inhibition of p38 kinase may be effective in the treatmentof certain viral conditions such as influenza (K. Kujime, et al., J.Immunology., 164, 3222-3228 (2000)), rhinovirus (S. Griego, et al., J.Immunology, 165, 5211-5220 (2000)), and HIV (L. Shapiro, et al., Proc.Natl. Acad. Sci. USA, 95, 7422-7426, (1998)).

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. It willbe recognized by one of skill in the art that the individual steps inthe following schemes may be varied to provide the compounds of FormulaI. The particular order of steps required to produce the compounds ofFormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Some substituents have been eliminated in the followingschemes for the sake of clarity and are not intended to limit theteaching of the schemes in any way.

p-Fluoronitrobenzene (a) is reacted with an N-protected (PG)hydroxypiperidine, an alkali hydroxide, and a tetraalkylammonium salt asphase transfer catalyst in a polar protic solvent, preferably water, toprovide the corresponding nitrophenyl substituted piperidine (b)(Methods for introducing and removing nitrogen protecting groups arewell known in the art; see, for example, Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley and Sons, New York,Chapter 7 (1999)). The nitro moiety is reduced with hydrogen or reducingagents, e.g., palladium catalysis, hydrogen, in a suitable solvent suchas lower alkanols to provide the corresponding amine (c). This amine isthen reacted with an appropriate pyrazolyl-2,2,2-trichloroethylcarbamate to provide an N-protected-piperidine substituted urea (d).After deprotection, the procedure provides the substituted piperidine(e). Finally, the substituted piperidine (e) is reacted with asubstituted carboxylic acid under the standard coupling conditions fororganic acids and organic amines in the presence of a dehydrating orcoupling agent, such as, a carbonyl diimidazole; or with a substitutedacid chloride or sulfonyl chloride and a base scavenger to provideFormula I (i). Furthermore, piperidine (e) may be alkylated with e.g.,methyliodide in the presence of a base scavenger [March, AdvancedOrganic Chemistry, 5^(th) Ed., John Wiley and Sons, New York (2001)] toprovide Formula I (i). The skilled artisan will appreciate that examplesof Formula I may be prepared by 1) beginning with otherfluoronitrobenzene isomers; 2) beginning with other protected piperidineisomers, including different N-protecting groups which may require otherdeprotection procedures to form intermediate (e); and 3) reacting amine(c) with other reactive carbamates or isocyanates.

1,3-Difluoronitrobenzene (k) is reacted with an N-protected (PG)hydroxypiperidine, an alkali hydroxide, and a tetraalkylammonium salt asphase transfer catalyst in a polar protic solvent, preferably water, toprovide the corresponding nitrophenyl substituted piperidine (1). Thenitro moiety is reduced with hydrogen or reducing agents, e.g.,palladium catalysis, hydrogen, in a suitable solvent such as loweralkanols to provide the corresponding amine (m). This amine is thenreacted with an appropriate pyrazolyl-2,2,2-trichloroethyl carbamate toprovide an N-protected-piperidine substituted urea (n). Afterdeprotection, the procedure provides the substituted piperidine (o).Finally, the substituted piperidine (o) is reacted with a substitutedcarboxylic acid under the standard coupling conditions for organic acidsand organic amines in the presence of a dehydrating or coupling agent,such as, a carbonyl di-imidazole; or with a substituted acid chloride orsulfonyl chloride and a base scavenger to provide Formula I (ii). Theskilled artisan will appreciate that examples of Formula I may beprepared by 1) beginning with other fluoronitrobenzene isomers ofintermediate (k); 2) beginning with other protected piperidine isomers;and 3) reacting amine (m) with other active carbamates or isocyanates.

A hydroxypiperidine (q) is reacted with an appropriately substitutedcarboxylic acid chloride, sulfonyl chloride, or protecting group, e.g.,benzyloxychlorocarbonyl in a suitable solvent such as methylene chlorideand organic base such as triethylamine to provide the correspondingN-substituted hydroxypiperidine (r). The substituted piperidine (r) istreated with an N-protected amino-phenol or an N-protectedamino-naphthol under Mitsunobu conditions [March, Advanced OrganicChemistry, 5^(th) Ed., John Wiley and Sons, New York (2001)] to providethe corresponding phenyl ether (s). After selective deprotection of theaniline fragment, the procedure provides the amine (t). Finally, theamine is reacted with an appropriate pyrazolyl isocyanate or carbamicacid, 222-trichloroethyl ester to provide Formula I (i, ii. iii). Theskilled artisan will appreciate that examples of Formula I (i, ii, andiii) may be prepared by 1) beginning with other piperidine isomers ofintermediate (q); and 2) using other isomers of aminophenol(s) oraminonaphthol(s) to form phenyl or naphthylethers.

An N-protected amino-piperidine (u) is reacted with a substitutedcarboxylic acid under the standard coupling conditions for organic acidsand organic amines in the presence of a dehydrating or coupling agent,such as, a carbonyl diimidazole to give the ring nitrogen substitutedpiperidine (v). After deprotection, the procedure provides the amine(w). Finally, the amine is reacted with an appropriate pyrazolylisocyanate or carbamic acid, 222-trichloroethyl ester to provide I (iv).The skilled artisan will appreciate that examples of Formula I may beprepared by beginning with other piperidine isomers of intermediate (u).

The intermediate (y), prepared from (g) and an isocyanato-benzoic acidethyl ester, is reduced in a suitable solvent such as THF with DIBAL togive the benzyl alcohol (z). The benzyl alcohol is oxidized to thealdehyde (aa) with, e.g., MnO₂ in methylene chloride. The carboxaldehydeis treated with piperazine under reducing conditions, e.g., with sodiumborohydride in methylene chloride to give the amine (bb), which isreacted with a substituted carboxylic acid under the standard couplingconditions for organic acids and organic amines in the presence of adehydrating or coupling agent, such as, a carbonyl diimidazole to giveFormula I (v, vi). The skilled artisan will appreciate that examples ofFormula I may be prepared by 1) beginning with other ureas or ureaisomers of intermediate (y); 2) using other reducing conditions, e.g.,catalytic hydrogenation, to form (z); and 3) using other oxidationconditions, e.g., Swern conditions when appropriate to form (aa).

Alternately, the ester fragment of intermediate (y) may be saponified,with alkali hydroxide in a lower alkanol to the acid (cc), and the acidis reacted with a mono-substituted piperazine in the presence of adehydrating or coupling agent, such as, a carbonyl diimidazole to giveFormula I (v).

p-Nitrobenzylbromide (a) is reacted with the N-BOC protected piperazinein potassium carbonate in a polar solvent, preferably acetonitrile toprovide the corresponding nitrobenzyl substituted piperazine (b). Thenitro moiety is reduced with tin chloride in ethyl acetate to providethe corresponding amine (c). This amine is then reacted with anappropriate pyrazolyl-2,2,2-trichloroethyl carbamate to provide anN-BOC-piperazine substituted urea (d). After deprotection, the procedureprovides the substituted piperazine (e). Finally, the substitutedpiperazine (e) is reacted with a substituted carboxylic acid under thestandard coupling conditions for organic acids and organic amines in thepresence of a dehydrating or coupling agent, such as carbonyldiimidazole; or with a substituted acid chloride in the presence of abase scavenger to give formula I(v). Furthermore, piperazine (e) may beacylated with e.g. acetic anhydride in the presence of a base to provideFormula I (v).

4-Nitro phenyl piperazine is protected as N-BOC derivative followed byreduction of the nitro group under hydrogenation conditions, typicallycatalyzed by Pd on carbon. This amine is then reacted with anappropriate pyrazolyl-2,2,2-trichloroethyl carbamate to provide anN-protected-piperazine substituted urea. After deprotection, theprocedure provides the substituted piperazine. Finally, the substitutedpiperidine is reacted with a substituted carboxylic acid under thestandard coupling conditions for organic acids and organic amines in thepresence of a dehydrating or coupling agent, such as, a carbonyldiimidazole; or with a substituted acid chloride or sulfonyl chlorideand a base scavenger to provide the final compounds

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of Formula I will tolerate certainreaction conditions employed to synthesize the compounds. These moietiesmay be introduced at a convenient point in the synthesis, or may beprotected and then deprotected as necessary or desired. The skilledartisan will appreciate that the protecting groups may be removed at anyconvenient point in the synthesis of the compounds of the presentinvention. Methods for introducing and removing nitrogen and oxygenprotecting groups are well known in the art; see, for example, Greeneand Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons, New York, Chapter 7 (1999). Furthermore, the skilled artisanwill appreciate that in many circumstances, the order in which moietiesare introduced is not critical. The particular order of steps requiredto produce the compounds of Formula I is dependent upon the particularcompound being synthesized, the starting compound, and the relativelability of the substituted moieties.

The abbreviations, symbols and terms used in the examples and assayshave the following meanings.

AcOH=acetic acid

DCC=dicyclohexylcarbodiimide

DEAD=Diethylazodicarboxylate

DIBAL=diisobutylaluminum hydride

DIEA=N,N-di-isopropylethylamine

DMSO=dimethylsulfoxide

DMF=N,N-dimethylformamide

hr=hour(s)

HCl=hydrochloric acid

HOB(t)=1-hydroxybenzotriazole

MnO₂=manganese dioxide

min=minute(s)

NaCl=sodium chloride

NaBH(OAc)₃=sodium triacetoxyborohydride

NaOH=sodium hydroxide

PS-DCC=carbodiimide bound to a solid phase

THF=tetrahydrofuran

PREPARATIONS Preparation 1 4-(4-Nitro-phenoxy)-piperidinyl-1-carboxylicacid tert-butyl ester

4-Hydroxy-1-piperidine-1-carboxylic acid tert-butyl ester (6.04 g, 30mmol) is dissolved in 1-fluoro-4-nitrobenzene (7.83 g, 55.5 mmol). Thenan aqueous potassium hydroxide solution (25% wt, 44 mL) is added,followed by addition of tetrabutylammonium bromide (1.26 g). Thereaction mixture is stirred at 35° C. for 17 hours. The yellow solid iscollected by filtration, washed with water (4×50 mL). A yellow powder isobtained (9.43 g, 97.5% yield).

Preparation 2 4-(4-Amino-phenoxy)-piperidinyl-1-carboxylic acidtert-butyl ester

A mixture of 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butylester (3.15 g, 9.77 mmol) and 10% wt palladium on carbon (1.01 g) inanhydrous ethanol-methanol (1:1, 100 mL) is stirred vigorously underhydrogen gas at 22° C. for 2 hours. Then the palladium on carbon isremoved by filtration. The filtrate is concentrated to give a whitesolid (2.35 g, 82.3% yield).

Preparation 3 (5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester

To an ice-cooled solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine(0.50 g, 3.26 mmol) and pyridine (0.27 mL, 3.29 mmol) in THF (THF, 10mL) is added 2,2,2-trichloroethyl chloroformate (0.44 mL, 3.29 mmol).The reaction mixture is stirred at 0° C. for 30 min and then warmed toroom temperature for 2 hours. Then the reaction mixture is distributedbetween ethyl acetate (100 mL) and water (100 mL). The aqueous phase isextracted with ethyl acetate (50 mL). The combined organic phases arewashed with saturated NaCl (2×50 mL) and dried over anhydrous magnesiumsulfate. After removal of solvent, the residue is purified on a silicagel chromatography by washing with ethyl acetate to provide a whitesolid (0.83 g, 78%, ES+(m/z) 329.9 [M+H]).

Preparation 41-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(piperidin-4-yloxy)-phenyl]-urea

1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(tert-butoxy)carbonyl-piperidin-4-yloxy]phenyl}urea(Example 1. below, 2.25 g, 4.77 mmol) is suspended in a solution oftrifluoroacetic acid in dichloromethane (25% v/v, 100 mL). The reactionmixture is stirred at 22° C. for 15 min. After removal of the solvent,the oily residue is neutralized with sodium hydroxide solution to pH 12and extracted with dichloromethane (6×50 mL). The combined-organicphases are dried over anhydrous sodium sulfate and concentrated to yielda yellow solid (2.28 g, ES+(m/z) 372.1 [M+H]).

Preparation 5 (2,6-Dichlorobenzoyl)-(4-hydroxy-piperidin-1-yl)-methanone

To an ice-cooled solution of 4-hydroxypiperidine (2.04 g, 20.2 mmol) andtriethylamine (3.2 mL, 23.0 mmol) in dichloromethane (25 mL) is added2,6-dichlorobenzoyl chloride (2.9 mL, 20.2 mmol). The reaction mixtureis stirred at 0° C. for 2 hours and then washed with 1 N aqueoushydrochloric acid solution (50 mL), water (50 mL), and an aqueoussaturated sodium bicarbonate solution (50 mL). The organic phase isdried over anhydrous sodium sulfate and concentrated to give a whitesolid (5.01 g, 90.5% yield, ES+(m/z) 276.1 [M+]).

Preparation 6 (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester

To a solution of 4-aminophenol (10.97 g, 100.5 mmol) and triethylamine(30 mL) in methanol (200 mL) is added di-tert-butyl dicarbonate (24.07g, 110.3 mmol). The reaction mixture is stirred at 22° C. for 14 hours.After removal of solvent, the residue is distributed between ethylacetate (250 mL) and 0.25 N aqueous hydrochloric acid solution (100 mL).The organic phase is isolated, washed with an aqueous saturated ammoniumchloride solution (3×50 mL), and dried over anhydrous sodium sulfate.Removal of solvent affords a white solid (20.91 g, 100% yield, ES−(m/z)208.1 [M−H]).

Preparation 7{4-[1-(2,6-Dichloro-benzoyl)-piperidin-4-yloxy]-phenyl}-carbamic acidtert-butyl ester

To an ice-cooled solution of (4-hydroxy-phenyl)-carbamic acid tert-butylester (422.8 mg, 2.02 mmol),(2,6-dichlorobenzoyl)-(4-hydroxy-piperidin-1-yl)-methanone (552.8 mg,2.01 mmol), and triphenylphosphine (1.09 g, 4.16 mmol) in THF (20 mL) isadded diethyl azodicarboxylate (1.0 mL, 2.20 mmol). The reaction mixtureis stirred at 22° C. for 17 hours. After removal of solvent, the residueis purified on a silica gel chromatography with ethyl acetate-hexanes toprovide a white solid (606.2 mg, 64.8% yield, ES+(m/z) 465.1 [M+H]).

Preparation 8[4-(4-Amino-phenoxy)-piperidin-1-yl]-(2,6-dichlorophenyl)-methanone

The above white solid,{4-[1-(2,6-dichloro-benzoyl)-piperidin-4-yloxy]-phenyl}-carbamic acidtert-butyl ester, is suspended in a solution of trifluoroacetic acid indichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at 22°C. for 15 min. After removal of the solvent, the oily residue isneutralized with 0.5 N aqueous sodium hydroxide solution (50 mL) andextracted with dichloromethane (5×50 mL). The combined organic phasesare dried over anhydrous sodium sulfate and concentrated to yield ayellow solid (440.2 mg, 92.0% yield, ES+(m/z) 365.1 [M+H]).

The following preparations are prepared with methods analogous tomethods in Preparations 5-8:

Method(s) No. Intermediate name Analogous to: Preparation 9[4-(4-Amino-phenoxy)-piperidin-1-yl]- Preparation 5-8 starting(2-chlorophenyl)-methanone with 2-chlorobenzoyl chloride in Prep. 5Preparation 10 [4-(4-Amino-phenoxy)-piperidin-1-yl]- Preparation 5-8starting (2,6-difluorophenyl)-methanone with 2,6-difluorobenzoylchloride in Prep. 5 Preparation 11 [4-(4-Amino-phenoxy)-piperidin-1-yl]-Preparation 5-8 starting (cyclopropyl)-methanone withcyclopropylcarbonyl chloride in Prep. 5 Preparation 12[4-(4-Amino-naphthyloxy)-piperidin-1- Preparation 6-8 startingyl]-(2,6-dichlorophenyl)-methanone with 4-aminonaphthol in Prep. 6Preparation 13 [4-(4-Amino-naphthyloxymethyl)- Preparation 5-8 startingpiperidin-1-yl]-(2,6-dichlorophenyl)- with 4- methanonepiperidinylmethanol in Prep. 5 Preparation 14{4-[2-(4-Amino-naphthyloxy)ethyl]- Preparation 5-8 startingpiperidin-1-yl}-(2,6-dichlorophenyl)- with 4-piperidinylethanolmethanone in Prep. 5 Preparation 15[4-(3-Amino-phenoxy)-piperidin-1-yl]- Preparation 5-8 starting(2,6-dichlorophenyl)-methanone with 3-aminophenol in Prep. 6

Preparation 164-(5-Amino-2-methyl-phenoxy)-piperidin-1-yl)-(2-chloro-phenyl)-methanone

The intermediate is prepared by using Prep. 5-8 starting from2-chlorobenzoyl chloride in Prep. 5 and 5-amino-o-cresol in Prep. 6.(ES+(m/z) 345.2 [M+H]).

Preparation 17 4-[2-(Dimethylamino)-ethoxy]-benzoic acid methyl ester

To an ice-water cooled solution of 2-dimethylamino-ethanol (305.0 mg,3.0 mmol), 4-hydroxy-benzoic acid methyl ester (456.3 mg, 3.0 mmol), andtriphenylphosphine (1.59 g, 6.0 mmol) in THF (4 mL) is added DEAD (40%solution in toluene, 2.75 mL, 6.0 mmol) dropwise. After stirred at 22°C. overnight, the reaction mixture is passed through a SGX column,washed with methanol, and eluded with 2M ammonia in methanol. Removal ofthe solvent gives a crude product, which is used in the next stepwithout purification.

Preparation 18 4-[2-(Dimethylamino)-ethoxy]-benzoic acid

To a solution of 4-[2-(dimethylamino)-ethoxy]-benzoic acid methyl ester(3 mmol) in methanol (10 mL) is added a lithium hydroxide solution (2 M,20 mL). The reaction mixture is stirred at 22° C. for 15 min. Afterremoval of the solvent, the residue is re-dissolved in methanol, passedthrough a SCX column, washed with methanol, and eluded with 2M ammoniain methanol. After solvent is evaporated, a white solid is obtained (500mg, 80% yield, ES−(m/z) 208.2 [M−H]).

Preparation 19 4-(3-tert-Butoxycarbonylamino-phenoxy)-piperidin-1-ylcarboxylic acid benzyl ester

To an ice-cooled solution of 1,1-(azodicarbonyl) dipiperidine (18.08 g,71.7 mmol) in anhydrous THF (200 mL) is added via syringetributylphosphine (17.69 mL, 79.7 mmol) and allowed to stir for 2.5hours. To this ice-cooled mixture is added a solution of(3-hydroxy-phenyl)-carbamic acid tert-butyl ester (10.0 g, 47.8 mmol)and 4-hydroxy-piperidine-1-carboxylic acid benzyl ester (7.23 mL, 47.8mmol) in anhydrous THF (30 mL) causing a light yellow precipitate toform. The mixture is warmed to room temperature and stirred overnight.The mixture is filtered through a fritted funnel and washed solid withTHF (3×15 mL). After removal of solvent, the residue is purified on asilica gel chromatography with ethyl acetate-hexanes to provide a clearoil (11.8 g, 57.9% yield, ES+(m/z) 427.2 [M+H]).

Preparation 20 4(3-Amino-phenoxy)-piperidin-1-yl carboxylic acid benzylester

4-(3-tert-Butoxycarbonylamino-phenoxy)-piperidine-1-carboxylic acidbenzyl ester (11.8 g, 27.6 mmol) is dissolved in a solution oftrifluoroacetic acid in dichloromethane (25% v/v, 20 mL). The reactionmixture is stirred at 22° C. for 60 min. After removal of the solvent,the oily residue is dissolved in dichloromethane (250 mL) andneutralized with 0.2 N aqueous sodium hydroxide solution (250 mL) andextracted with dichloromethane (10×100 mL) followed by ethyl acetate(5×100 mL). The combined organic phases are dried over anhydrous sodiumsulfate. After removal of solvent, the crude product is purified onsilica gel chromatography with dichloromethane-methanol to give a lightbrown oil (4.84 g, 54%, ES+(m/z) 327.3 [M+H]).

Preparation 211-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[3-(piperidin-4-yloxy)-phenyl]-urea

A mixture of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(benzyloxy)-carbonyl-piperidin-4-yloxy]phenyl}urea.(Example 54. below, 6.62 g, 13.1 mmol) and 10% palladium on carbon (1 g)in ethanol (200 mL) is stirred at 22° C. under hydrogen gas for 2.5hours. The catalyst is removed by filtration. The filtrate isconcentrated to give brown oil, which solidifies upon standing at 22° C.over weekend. The residue is purified on a silica gel chromatography byeluting with methanol and dichloromethane. A peach color solid isobtained (3.51 g, 72% yield, ES+(m/z) 372.3 [M+H]).

Preparation 22 3-Nitro-5-trifluoromethyl-phenol

To a solution of 3-methyl-5-trifluoromethyl-nitrobenzene (3.80 g, 17.2mmol) in dichloromethane (10 mL) at −78° C. is added a solution of borontribromide (1M in DCM, 100 mL, 100 mmol). The reaction mixture isallowed to warm up to 22° C. and stirred overnight. Next, the reactionis quenched with a saturated sodium bicarbonate solution and extractedwith ethyl acetate (4×100 mL). The combined organic phases are driedover sodium sulfate and concentrated. The residue is purified on silicagel with hexanes-ethyl acetate to yield a yellow solid (2.6 g, 73%yield).

Preparation 231-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[3-(piperidin-4-yloxy)-5-trifluoromethyl-phenyl]-urea

The intermediate is synthesized by using the method of Preparation 7 and2, Example 1, and Preparation 4 from intermediate 22. (ES+(m/z) 440.2[M+H]).

Preparation 24 [1-(4-Methanesulfonyl-benzoyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

To an ice-cooled slurry of 4-N-BOC-amino-piperidine (400.8 mg, 2.0mmol), 1-hydroxybenzotriazole (HOBt, 342.3 mg, 2.53 mmol), andp-(methylsulfonyl)-benzoic acid (445.9 mg, 2.23 mmol) in dichloromethane(6 mL) is added 1,3-dicyclohexylcarbodiimide (DCC, 496.7 mg, 2.40 mmol).The reaction mixture is stirred at 22° C. for 23 hours. The crudeproduct is purified on a silica gel chromatography with ethylacetate-hexanes to provide a white solid (692.9 mg, 90.6% yield,ES+(m/z) 383.1 [M+H]).

Preparation 25(4-Amino-piperidin-1-yl)-(4-methanesulfonyl-phenyl)-methanone

The above white solid is suspended in a solution of trifluoroacetic acidin dichloromethane (25% v/v, 20 mL). The reaction mixture is stirred at22° C. for 15 min. After removal of the solvent, the oily residue isneutralized with 0.5 N aqueous sodium hydroxide solution and extractedwith dichloromethane (5×50 mL). The combined organic phases are driedover anhydrous sodium sulfate and concentrated to yield a white solid(308.1 g, 60.2% yield, ES+(m/z) 283.2 [M+H]).

Preparation 26[4-(3-Amino-phenyl)-piperidin-1-yl]-(2,6-dichloro-phenyl)-methanone

To an ice-cooled solution of 4-(3-aminophenyl)-piperidine hydrochloride(250.2 mg, 1.0 mmol) and triethylamine (1 mL) in dichloromethane (6 mL)is added 2,6-dichlorobenzoic chloride (0.15 mL, 1.0 mmol). The reactionmixture is stirred at 0° C. for 6 hours. After removal of solvent, theresidue is purified on a silica gel chromatography with ethylacetate-hexanes to provide a white solid (163.9 mg, 46.9% yield,ES+(m/z) 349.1 [M+H]).

Preparation 274-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethylester

To 1.0 g (6.53 mmol) of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine in 10mL of CH₂Cl₂ is added 1.37 g (7.17 mmol) of 4-isocyanate-benzoic acidethyl ester, and the mixture is stirred at 23° C. for 3 hours. The whitesolid is filtered and triturated with methylene chloride and then withdiethyl ether. The solids are air-dried 1 hour to obtain the titleproduct (2.07 g, 6.01 mmol, 92% yield, ES+(m/z) 345 [M+H]).

Preparation 281-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-hydroxymethyl-phenyl)urea

To a dry flask is added 872 mg (2.5 mmol) of4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethylester in 30 mL dry methylene chloride and cooled to 0° C. Next, 10.12 mLof 1M DIBAL in hexanes (4 eq., 10.12 mmol) is added and the reaction isallowed to reach room temperature. The mixture is then stirred for 1hour, and 60 mL of ethyl acetate and 100 mL of sodium tartrate saturatedaqueous solution are added, and the mixture is stirred for another 30min. Then the organic layer is separated and washed with water and driedover magnesium sulfate, filtered, and evaporated to a white solidweighing 720 mg (2.4 mmoles, 95%, ES+(m/z) 303 [M+H]).

Preparation 291-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-formyl-phenyl)-urea

To a suspension of 518 mg (1.72 mmol) of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-hydroxymethyl-phenyl)-ureain methylene chloride (25 mL) is added 2.7 g of MnO₂. The mixture isstirred at room temperature for 3 hours. Then the mixture is filteredover Celite® and evaporated to obtain 353 mg (1.2 mmol, 68%) of thetitle compound as a white solid. (ES+(m/z) 301 [M+H]).

Preparation 301-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-ylmethyl-phenyl)-ureadihydrochloride

To a suspension of 353 mg (1.18 mmol) of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-formyl-phenyl)-urea in1,2-dichloroethane (20 mL) is added piperazine-1-carboxylic acidtert-butyl ester (219 mg, 1.18 mmol). Next, NaBH(OAc)₃ is added (350 mg,1.65 mmol). The reaction mixture is stirred at room temperatureovernight. Then the mixture is diluted with methylene chloride and 10 mLof 1 N NaOH is added. The organic layer is separated and dried oversodium sulfate, filtered and evaporated at reduced pressure to afford485 mg of the N-BOC protected compound as a colorless oil. ES+(m/z)=471[M+H]. Then 10 mL of a 4M solution of HCl in dioxane is added and themixture is stirred for 2 hours at room temperature. The solvents areevaporated at reduced pressure to afford the title compound 457 mg (1.03mmol, 87%) as a white solid. (ES+(m/z) 371 [M+H].

Preparation 313-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethylester

Using the same procedure as in Preparation 27 and starting from3-Isocyanato-benzoic acid ethyl ester the title compound is synthesized.(ES+(m/z) 345 [M+H].

Preparation 321-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-hydroxymethyl-phenyl)-urea

Using the same procedure as in Preparation 28, starting from3-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-benzoic acid ethylester the title compound is synthesized. (ES+(m/z) 303 [M+H].

Preparation 331-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-formyl-phenyl)-urea

Using the same procedure as in Preparation 29, starting from1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-hydroxymethyl-phenyl)-ureathe title compound is synthesized. (ES+(m/z) 301 [M+H].

Preparation 341-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-piperazin-1-ylmethyl-phenyl)-ureadihydrochloride

Using the same procedure as in Preparation 30, starting from1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-formyl-phenyl)-urea thetitle compound is synthesized. (ES+(m/z) 371 [M+].

Preparation 354-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid

To a suspension of4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid ethylester (0.24 g, 0.71 mmol) in ethanol (4 mL) is added 1 N aq. NaOHsolution (2 mL) and the mixture is heated at 80° C. for 2 hours. Then, 1N HCl is added until pH 6 and the mixture is diluted with ethyl acetate.The organic phase is washed once with aqueous sodium chloride solutionand dried over magnesium sulfate, filtered and evaporated under reducedpressure to give 0.19 g (0.59 mmol), 83% as white solid. ES+(m/z) 317[M+H].

Preparation 36 5-tert-Butyl-2-isopropyl-2H-pyrazol-3-ylamine

To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (1 g, 7.99 mmol) andisopropyl hydrazine hydrochloride (873 mg, 7.99 mmol) in toluene (40 mL)is added DIEA (1.39 mL, 7.99 mmol). The reaction mixture is stirred at110° C. in a sealed tube overnight. After removal of solvent, theresidue is purified on a silica gel chromatography with ethylacetate-hexanes to give a white solid (1.14 g, 79% yield, ES+(m/z) 182[M+H]).

The following preparations are prepared with a method analogous toPreparation 36.

Intermediate ES+ Synthetic Method(s) No. Name R¹ m/z [M + H] Analogousto: Prep 2,5-Di-tert- tert-Butyl 196 Prep 36 with tert-butyl 37butyl-2H- hydrazine hydrochloride pyrazol- 3-ylamine Prep 5-tert-Butyl-Ethyl 168 Prep 36 with ethyl 38 2-ethyl-2H- hydrazine oxalate pyrazol-3-ylamine

The following preparations are prepared with a method analogous toPreparation 3:

ES+ m/z No. Intermediate Name R¹ [M + H] Prep(2,5-Di-tert-butyl-2H-pyrazol-3-yl)- tert-butyl 371 40 carbamic acid2,2,2-trichloro-ethyl ester Prep (5-tert-Butyl-2-ethyl-2H-pyrazol-3-yl)-Ethyl 343 41 carbamic acid 2,2,2-trichloro-ethyl ester Prep(5-tert-Butyl-2-isopropyl-2H-pyrazol- Isopropyl 357 42 3-yl)-carbamicacid 2,2,2-trichloro- ethyl ester Prep(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- Tolyl 406 43 carbamic acid2,2,2-trichloro-ethyl ester

Preparation 44 4-(4-Nitro-benzyl)-piperazinyl-1-carboxylic acidtert-butyl ester

A mixture of 1-Bromomethyl-4-nitro-benzene (2 g, 9.26 mmol), N-BOCpiperazine (1.72 g, 9.26 mmol) and potassium carbonate (2.8 g, 20.37mmol) in acetonitrile (25 mL) is stirred at 80° C. overnight. Then, thepotassium carbonate is removed by filtration. The filtrate isconcentrated to give a white solid (2.63 g, 89% yield, ES+(m/z) 322[M+H]).

Preparation 45 4-(4-Amino-benzyl)-piperazin-1-yl carboxylic acidtert-butyl ester

4-(4-Nitro-benzyl)-piperazin-1-yl carboxylic acid tert-butyl ester (769mg, 2.4 mmol) and tin chloride dihydrate (2.70 g, 12 mmol) are suspendedin ethyl acetate (20 mL) and stirred at room temperature overnight.Then, saturated aqueous solution of sodium bicarbonate (20 mL) is addedand vigorously stirred for 1 hour. Solids are removed by filtration andthe organic layer of the filtrate is separated and washed with water (20mL). The organic phase is dried over anhydrous magnesium sulfate andconcentrated to give a white solid (620 mg, 89% yield, ES+(m/z) 293[M+H]).

The following preparations are prepared using the method of Example 1(see below):

ES+ Synthetic m/z Method(s) No. Intermediate Name R¹ [M + H] Analogousto: Prep 4-{4-[3-(5-tert-Butyl- Iso- 499 Ex. 1 using cpd 462-isopropyl-2H-pyrazol-3- propyl from Prep 42 yl)-ureido]-benzyl}-piperazin-1-yl carboxylic acid tert-butyl ester Prep4-{4-[3-(5-tert-Butyl- Ethyl 485 Ex. 1 using cpd 472-ethyl-2H-pyrazol-3- from Prep 41 yl)-ureido]-benzyl}-piperazinyl-1-carboxylic acid tert-butyl ester

Preparation 481-(5-tert-Butyl-2-ethyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-ylmethyl-phenyl)-ureadihydrochloride

4-{4-[3-(5-tert-Butyl2-ethyl-2H-pyrazol-3-yl)-ureido]-benzyl}-piperazine-1-carboxylic acidtert-butyl ester (105 mg, 0.216 mmol) is dissolved in dichloromethane (3mL) and a 4M solution of HCl in 1,4-dioxane (0.86 mL, 3.5 mmol) is addedand the mixture stirred at room temperature for 2 hours. After removalof solvent, the residue is triturated with diethyl ether and air-driedto obtain the title compound (99 mg, 99% yield, ES+(m/z) 385 [M+H]).

The following preparation is prepared with method analogous toPreparation 48.

ES + Synthetic m/z Method(s) No. Intermediate Name R¹ [M + H] Analogousto: Prep 1-(5-tert-Butyl-2- Isopropyl 371 Preparation 48 49isopropyl-2H-pyrazol- 3-yl)-3-(4-piperazin- 1ylmethyl-phenyl)-urea

Preparation 50 4-(4-Nitro-phenyl)-piperazin-1-yl carboxylic acidtert-butyl ester

1-(4-Nitro-phenyl)-piperazine (2 g, 9.65 mmol) is dissolved indichloromethane (50 mL) and (BOC)₂O is added (2.10 g, 9.65 mmol). Themixture is stirred at room temperature overnight. Solvent removalaffords a yellow solid (2.96 g, 100% yield, ES+(m/z) 308 [M+H]).

Preparation 51 4-(4-Amino-phenyl)-piperazin-1-yl carboxylic acidtert-butyl ester

Using the same procedure as in Preparation 45 the title compound issynthesized. ES+(m/z) 278 [M+H]).

Preparation 524-{4-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-phenyl}-piperazin-1-ylcarboxylic acid tert-butyl ester

Using the method of Example 1 (see below) the title compound issynthesized ES+(m/z) 457 [M+H]).

Preparation 534-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-phenyl}-piperazin-1-ylcarboxylic acid tert-butyl ester

4-(4-Amino-phenyl)-piperazin-1-yl carboxylic acid tert-butyl ester (0.51g, 1.8 mmol) is dissolved in 20 mL of CH₃CN and K₂CO₃ (0.28 g, 2.02mmol) is added, followed by addition of(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (0.74 g, 2.02 mmol). Solution is stirredovernight at room temperature under N₂ atmosphere. Reaction mixture isdiluted by addition of CH₂Cl₂ (100 mL) and washed with saturated aqueoussolution of sodium chloride and water. The organic layer is dried overMgSO₄, and the solvent is evaporated under reduced pressure. Resultantcrude is purified by ISCO using a mixture CH₂Cl₂/MeOH as eluent. (0.72g, 75% yield, ES+(m/z) 533 [M+H]).

The following preparations are prepared with method analogous toPreparation 48:

Synthetic ES+ Method(s) m/z Analogous No. Intermediate Name R¹ [M + H]to: Prep 1-(5-tert-Butyl-2- Methyl 357 Prep 48 54 methyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl- phenyl)-urea dihydrochloride Prep1-(5-tert-Butyl-2- Tolyl 433 Prep 48 55 p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl- phenyl)-urea dihydrochlorideUsing essentially the methodology of Example 97 (see below) but withEt₃N and CH₂Cl₂ the following examples are prepared:

ES+ m/z Synthetic [M + Method(s) No. Name Y H] Analogous to: Prep1-(5-tert-Butyl-2- 2,6- 573 Ex. 97 with 2,6- 56p-tolyl-2H-pyrazol-3-yl)- difluoro- di-fluorobenzoyl3-{4-[4-(2,6-difluoro- benzoyl chloride benzoyl)-piperazin-1-yl]-phenyl}-urea Prep 1-(5-tert-Butyl-2- 2,6- 606 Ex. 97 with 2,6- 57p-tolyl-2H-pyrazol-3-yl)- dichloro- di-chlorobenzoyl3-{4-[4-(2,6-dichloro- benzoyl chloride benzoyl)-piperazin-1-yl]-phenyl}-urea Prep 1-(5-tert-Butyl-2- Cyclo- 501 Ex. 97 with 58p-tolyl-2H-pyrazol-3-yl)- propyl- cyclopropyl- 3-[4-(4- carbonylcarbonyl- cyclopropyl-piperazin-1- chloride yl)-phenyl]-urea Prep1-[4-(4-tert-Butyl- tert-Butyl 517 Ex. 97 with 59piperazin-1-yl)-phenyl]- carbonyl pivaloyl 3-(5-tert-butyl-2-p- chloridetolyl-2H-pyrazol- 3-yl)-urea

Using essentially the methodology of Example 128 (see below) (reactionof1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl-phenyl)-ureawith the corresponding carboxylic acid) the following compound isprepared.

ES+ m/z Synthetic [M + Method(s) No. Name Y H] Analogous to: Prep1-(5-tert-Butyl-2-p-tolyl- Isobutyric 503 Example 128 602H-pyrazol-3-yl)-3-[4- acid (4-isobutyryl-piperazin-1-yl)- phenyl]-urea

Preparation 61 1-Bromomethyl-2-fluoro-4-nitro-benzene

To a solution of 2-Fluoro-1-methyl-4-nitro-benzene (1 g, 6.45 mmol) andsodium bromate (2.92 g, 19.33 mmol) in an EtOAc:water (12 mL:9 mL)mixture, is added dropwise via addition funnel a 3.85M solution ofsodium bisulfite 5.20 mL, 19.33 mmol). The mixture is vigorously stirredfor six days and then sodium bisulfite (10 mL) is added and organiclayer separated and washed with aqueous saturated solution of sodiumbicarbonate. The organic phase is dried with magnesium sulfate, filteredand evaporated at reduced pressure to afford a mixture of title compoundand starting 2-fluoro-1-methyl-4-nitro-benzene in a 5:1 ratio (1H-NMR)which is used in the next step without further purification. ES+(m/z)235 [M+H]).

Preparation 62 4-Bromomethyl-2-fluoro-1-nitro-benzene

Using the same procedure as in Preparation 56, but starting from2-fluoro-4-methyl-1-nitro-benzene, the title compound is synthesized.ES+(m/z) 235 [M+H]).

Using the same procedure as in Preparation 44, followed by Preparation48, the following compounds are prepared:

ES + Synthetic m/z Method(s) No. Intermediate Name [M + H] Analogous to:Prep 1-(3-Fluoro-4-nitro-benzyl)- 240 Prep 44, and 63 piperazinedihydrochloride then Prep 48 Prep 1-(2-Fluoro-4-nitro-benzyl)- 240 Prep44, and 64 piperazine dihydrochloride then Prep 48Using essentially the methodology of Example 97 (see below) thefollowing compounds are prepared:

ES + Synthetic m/z Method(s) No. Intermediate Name [M + H] Analogous to:Prep (2,6-Difluoro-phenyl)-[4-(2-fluoro-4- 380 Ex. 97 with 2,6-di- 65nitro-benzyl)-piperazin-1-yl]-methanone fluorobenzoyl chloride Prep(2,4-Difluoro-phenyl)-[4-(2-fluoro-4- 380 Ex. 97 with 2,4-di- 66nitro-benzyl)-piperazin-1-yl]-methanone fluorobenzoyl chloride Prep(2,6-Difluoro-phenyl)-[4-(3-fluoro-4- 380 Ex. 97 with 2,6-di- 67nitro-benzyl)-piperazin-1-yl]-methanone fluorobenzoyl chloride Prep(2,6-Dichloro-phenyl)-[4-(3-fluoro-4- 413 Ex. 97 with 2,6-di- 68nitro-benzyl)-piperazin-1-yl]-methanone chlorobenzoyl chloride Prep(2,4-Difluoro-phenyl)-[4-(3-fluoro-4- 380 Ex. 97 with 2,4-di- 69nitro-benzyl)-piperazin-1-yl]-methanone fluorobenzoyl chlorideUsing the same procedure as in Preparation 45, the following compoundsare synthesized:

ES + Synthetic m/z Method(s) No. Intermediate Name [M + H] Analogous to:Prep [4-(4-Amino-2-fluoro-benzyl)-piperazin- 350 Preparation 45 701-yl]-(2,6-difluoro-phenyl)-methanone Prep[4-(4-Amino-2-fluoro-benzyl)-piperazin- 350 Preparation 45 711-yl]-(2,4-difluoro-phenyl)-methanone Prep[4-(4-Amino-3-fluoro-benzyl)-piperazin- 350 Preparation 45 721-yl]-(2,6-difluoro-phenyl)-methanone Prep[4-(4-Amino-3-fluoro-benzyl)-piperazin- 383 Preparation 45 731-yl]-(2,6-dichloro-phenyl)-methanone Prep[4-(4-Amino-3-fluoro-benzyl)-piperazin- 350 Preparation 45 741-yl]-(2,4-difluoro-phenyl)-methanone

EXAMPLES Example 11-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(tert-butoxy)carbonyl-piperidin-4-yloxy]phenyl}urea

Nitrogen gas is bubbled through a solution of(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (1.65 g, 5.01 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.47g, 5.02 mmol) in DMSO (20 mL) for 2 min. Next, N,N-diisopropylethylamine(2 mL, 11.48 mmol) is added. The reaction mixture is stirred at 60° C.for 6 hours. Then, the reaction mixture is distributed between water(150 mL) and dichloromethane (100 mL). The aqueous layer is isolated andextracted with dichloromethane (2×100 mL). The combined organic phasesare washed with water (100 mL) and aqueous sodium chloride (100 mL), anddried over anhydrous sodium sulfate. After removal of solvent, the crudeproduct is purified on a silica gel chromatography with ethylacetate-hexanes (25%) to give a white solid (2.28 g, 97%, ES−(m/z) 470.1[M−H]).

Example 21-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(benzoyl)-piperidin-4-yloxy]phenyl}urea

To an ice-cooled solution of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(piperidin-4-yloxy)-phenyl]-urea(82.2 mg, 0.22 mmol), 1-hydroxybenzotriazole (HOBt, 50.1 mg, 0.37 mmol),and benzoic acid (38.8 mg, 0.32 mmol) in dichloromethane-THF (1:1, 2 mL)is added DCC (52.0 mg, 0.25 mmol). The reaction mixture is stirred at22° C. for 19 hours. The crude product is purified on a silica gelchromatography with ethyl acetate-hexanes to provide a white solid (97.7mg, 93.4% yield, ES+(m/z) 476.1 [M+H]).

Example 31-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]phenyl}urea

Nitrogen gas is bubbled through a solution of[4-(4-amino-phenoxy)-piperidin-1-yl]-(2,6-dichlorophenyl)-methanone (47mg, 0.12 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (42 mg, 0.12 mmol) in DMSO (1.5 mL) for 5min. Next, N,N-diisopropylethylamine (40 μL, 0.24 mmol) is added. Thereaction mixture is stirred at 60° C. for 6 hours. Then, DMSO is removedby passing the reaction mixture through an SCX column. The crude productis obtained by eluting the SCX column with 2M ammonia in methanol andpurifying the residue on silica gel with ethyl acetate-hexanes (25%) togive a white solid (ES+(m/z) 544.2 [M+H]).

Using the method of Example 2 or 3 gives the following compounds,isolated as the free base, wherein the urea nitrogen is always connectedto a carbon atom in W′:

Synthetic ES+ Method(s) Ex. m/z Analogous No. Name R¹ W′ Y [M + H] to: 41-(5-tert-Butyl-2-methyl- Me 1,4- Cyclo- 440.2 Ex 2 using2H-pyrazol-3-yl)-3-{4- phenyl- propyl YOH [1-(cyclopropyl)carbonyl- O—carbonyl piperidin-4- yloxy]phenyl}urea 5 1-(5-tert-Butyl-2-methyl- Me1,4- Isopropyl 442.1 Ex 2 using 2H-pyrazol-3-yl)-3-{4- phenyl- carbonylYOH [1-(isopropyl)carbonyl- O— piperidin-4- yloxy]phenyl}urea 61-(5-tert-Butyl-2-methyl- Me 1,4- tert-Butyl 456.3 Ex 2 using2H-pyrazol-3-yl)-3-{4- phenyl- carbonyl YOH [1-(tert-butyl)carbonyl- O—piperidin-4- yloxy]phenyl}urea 7 1-(5-tert-Butyl-2-methyl- Me 1,4- 4-477.1 Ex 2 using 2H-pyrazol-3-yl)-3-{4- phenyl- Pyridinyl YOH[1-(pyridin-4- O— carbonyl yl)carbonyl-piperidin-4- yloxy]phenyl}urea 81-(5-tert-Butyl-2-methyl- Me 1,4- Cyclo- 468.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- pentyl YOH (cyclopentyl)carbonyl- O—carbonyl piperidin-4- yloxy]phenyl}urea 9 1-(5-tert-Butyl-2-methyl- Me1,4- 3- 482.2 Ex 2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Thienyl- YOH(3-thienyl)carbonyl- O— carbonyl piperidin-4- yloxy]phenyl}urea 101-(5-tert-Butyl-2-methyl- Me 1,4- 2- 528.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Chloro- YOH(2-chloro-6-fluorobenzoyl)- O— 6-fluoro- piperidin-4- benzoylyloxy]phenyl}urea 11 1-(5-tert-Butyl-2-methyl- Me 1,4- 4- 466.2 Ex 2using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Imidazolyl YOH(imidazol-4-yl)carbonyl- O— carbonyl piperidin-4- yloxy]phenyl}urea 121-(5-tert-Butyl-2-methyl- Me 1,4- 4- 466.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Pyrazolyl YOH (pyrazol-4-yl)carbonyl-O— carbonyl piperidin-4- yloxy]phenyl}urea 13 1-(5-tert-Butyl-2-methyl-Me 1,4- 2- 544.2 Ex 2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Trifluoro-YOH (2-trifluoromethyl O— methyl benzoyl)-piperidin-4- benzoylyloxy]phenyl}urea 14 1-(5-tert-Butyl-2-methyl- Me 1,4- 2- 560.2 Ex 2using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Trifluoro- YOH (2- O— methoxytrifluoromethoxybenzoyl)- benzoyl piperidin-4- yloxy]phenyl) urea 151-(5-tert-Butyl-2-methyl- Me 1,4- 2-Fluoro 494.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- benzoyl YOH(2-fluorobenzoyl)-piperidin- O— 4-yloxy]phenyl}urea 161-(5-tert-Butyl-2-methyl- Me 1,4- 2-(5- 516.1 Ex 2. using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Chloro- YOH (5-chlorothien-2- O—thienyl) yl)carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 171-(5-tert-Butyl-2-methyl- Me 1,4- 3-(2- 507.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[- phenyl- Methoxy- YOH (2-methoxypyridin-3- O—pyridinyl) yl)carbonyl-piperidin-4- carbonyl yloxy]pheny1}urea 181-(5-tert-Butyl-2-methyl- Me 1,4- 1-Phenyl- 516.3 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- cyclo- YOH (1-phenylcyclopropyl) O—propyl carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 191-(5-tert-Butyl-2-methyl- Me 1,4- 5-(2- 507.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Methoxy- YOH (2-methoxypyridin-5- O—pyridinyl) yl)carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 201-(5-tert-Butyl-2-methyl- Me 1,4- 5-(2- 511.1 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Chloro YOH (2-chloropyridin-5- O—pyridinyl) yl)carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 211-(5-tert-Butyl-2-methyl- Me 1,4- 3- 465.2 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Pyrrolyl YOH (pyrrol-3-yl)carbonyl- O—carbonyl piperidin-4- yloxy]phenyl}urea 22 1-(5-tert-Butyl-2-methyl- Me1,4- 3-(2- 511.2 Ex 2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Chloro-YOH (2-chloropyridin-3- O— pyridinyl) yl)carbonyl-piperidin-4- carbonylyloxy]phenyl}urea 23 1-(5-tert-Butyl-2-methyl- Me 1,4- 3-(2,6- 537.3 Ex2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Di- YOH(2,6-dimethoxypyridin-3- O— methoxy- yl)carbonyl-piperidin-4- pyridinyl)yloxy]phenyl}urea carbonyl 24 1-(5-tert-Butyl-2-methyl- Me 1,4-4-(1,3,5- 508.3 Ex 2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Tri- YOH(1,3,5-trimethylpyrazol-4- O— methyl- yl)carbonyl-piperidin-4-pyrazolyl) yloxy]phenyl}urea carbonyl 25 1-(5-tert-Butyl-2-methyl- Me1,4- 2-(3- 496.2 Ex 2 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Methyl-YOH (3-methylthien-2- O— thienyl) yl)carbonyl-piperidin-4- carbonylyloxy)phenyl}urea 26 1-(5-tert-Butyl-2-methyl- Me 1,4- 2-(3- 516.2 Ex 2using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- Chloro- YOH (3-chloro-thien-2-O— thienyl) yl)carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 271-(5-tert-Butyl-2-methyl- Me 1,4- 4-(3,5- 545.1 Ex 2 using2H-pyrazol-3-yl)-3-{4-[1- phenyl- Dichloro- YOH (3,5-dichloropyridin-4-O— pyridinyl) yl)carbonyl-piperidin-4- carbonyl yloxy]phenyl}urea 281-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2,6-Dichloro-benzoyl 562.3 Ex 1 & 2startingwith3,5-difluoro-nitrobenzene inPrep 1 291-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2-chlorobenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2-Chloro-benzoyl 528.3 Ex 28usingYOH 301-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2-trifluoromethylbenzoyl)-piperidin-4-yloxy]-phenyl}ureaMe

2-Trifluoro-methyl-benzoyl 562.3 Ex 28using YOH 311-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2,6-difluorobenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2,6-difluoro-benzoyl 530.3 Ex 28usingYOH 321-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2-fluorobenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2-Fluoro-benzoyl 512.3 Ex 28usingYOH 331-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2-fluoro-6-chlorobenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2-Chloro-6-fluoro-benzoyl 546.3 Ex 28usingYOH 341-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(2-trifluoromethoxybenzoyl)-piperidin-4-yloxy]phenyl}ureaMe

2-Trifluoro-methoxy-benzoyl 578.3 Ex 28usingYOH 351-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(benzoyl)-piperidin-4-yloxy]phenyl}ureaMe

Benzoyl 494.3 Ex 28 usingYOH 361-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{5-fluoro-3-[1-(3-pyrrolyl)carbonyl-piperidin-4-yloxy]phenyl}ureaMe

3-Pyrrolyl-carbonyl 483.3 Ex 28 usingYOH 37 1-(5-tert-Butyl-2-methyl- Me1,4- Methylsulfonyl 450.1 From 2H-pyrazol-3-yl)-3-[4-(1- phenyl- MeSO₂Clmethanesulfonyl-piperidin- O— acylation of 4-yloxy)-phenyl]urea1-(5-tert- butyl-2- methyl-2H- pyrazol-3- yl)-3-[4- (piperidin-4-yloxy)- phenyl]-urea 38 1-(5-tert-Butyl-2-methyl- Me 1,4- 2-Chloro-510.1 Ex. 3 using 2H-pyrazol-3-yl)-3-{4-[1- phenyl- benzoyl [4-(4-(2-chlorobenzoyl)- O— Amino- piperidin-4- phenoxy)- yloxy]phenyl}ureapiperidin-1- yl]-(2-chloro phenyl)- methanone 39 1-(5-tert-Butyl-2- Me1,4- 2,6- 512.1 Ex. 3 using [4-(4- methyl-2H-pyrazol- phenyl- Difluoro-Amino-phenoxy)- 3-yl)-3-{4-[1-(2,6- O— benzoyl piperidin-1-yl]-difluorobenzoyl)- (2,6-difluoro piperidin-4- phenyl)- yloxy]phenyl}ureamethanone 40 1-(5-tert-Butyl-2-p- p- 1,4- 2,6- 621.9 Ex. 3 using (5-tolyl-2H-pyrazol-3- tolyl phenyl- Dichloro- tert-butyl-2-tolyl-yl)-3-{4-[1-(2,6- O— benzoyl 2H-pyrazol-3-yl)- dichlorobenzoyl)-carbamic acid piperidin-4- 2,2,2-trichloro- yloxy]phenyl}urea ethylester 41 1-(5-tert-Butyl-2-p- p- 1,4- Cyclopropyl 516.1 Ex. 40 using [4-tolyl-2H-pyrazol-3- tolyl phenyl- carbonyl (4-Amino- yl)-3-{4-[1- O—phenoxy)- (cyclopropyl)carbonyl- piperidin-1-yl]- piperidin-4-(cyclo-propyl)- yloxy]phenyl}urea methanone 42 1-(5-tert-Butyl-2-p- p-1,4- 2,6- 670.2 Ex. 40 using [4-(4- tolyl-2H-pyrazol-3- tolyl naphthyl-Dichloro- Amino-naphthyl-oxy)- yl)-3-{4-[1-(2,6- O— benzoylpiperidin-1-yl]-(2,6- dichlorobenzoyl)- dichloro-phenyl)-piperidin-4-yloxy]-1- methanone naphthyl}-urea. 43 1-(5-tert-Butyl-2-p-p- 1,4- 2,6- 684.2 Ex. 42 using [4-(4- tolyl-2H-pyrazol-3- tolylnaphthyl- Dichloro Amino-naphthyl- yl)-3-{4-[1-(2,6- OCH₂— benzoyloxymethyl)-piperidin- dichlorobenzoyl)- 1-yl]-(2,6-dichloro-piperidin-4- phenyl)-methanone ylmethoxy]- naphthyl}-urea. 441-(5-tert-Butyl-2-p- p- 1,4- 2,6- 698.3 Ex. 42 using {4-[2-(4-tolyl-2H-pyrazol-3- tolyl naphthyl- Dichloro- Amino- yl)-3-{4-[1-(2,6-OCH₂CH₂ benzoyl naphthyloxy)ethyl]- dichlorobenzoyl)-piperidin-1-yl}-(2,6- piperidin-4- dichloro-phenyl)- ylethoxy]-methanone naphthyl}-urea. 45 1-(5-tert-Butyl-2- Me 1,3- 2,6- 544.0 Ex. 3using [4-(3- methyl-2H-pyrazol-3- phenyl- Dichloro- Amino-phenoxy)-yl)-3-{3-[1-(2,6- O— benzoyl piperidin-1-yl]-(2,6- dichlorobenzoyl)-dichloro piperidin-4- phenyl)-methanone yloxy]phenyl}urea 461-(5-tert-Butyl-2- Me 1,3- 2- 510.2 Ex. 2 using YOH methyl-2H-pyrazol-3-phenyl- Chloro- yl)-3-{3-[1-(2- O— benzoyl chlorobenzoyl)- piperidin-4-yloxy]phenyl}urea 47 1-(5-tert-Butyl-2-methyl-2H- Me 1,3- 2,6-Difluoro-512.3 Ex. 2 pyrazol-3-yl)-3-{3-[1-(2,6- phenyl- benzoyl usingdifluorobenzoyl)-piperidin-4- O— YOH yloxy]phenyl}urea 481-(5-tert-Butyl-2-methyl-2H- Me 1,3- 2-Chloro-6- 528.2 Ex. 2pyrazol-3-yl)-3-{3-[1-(2- phenyl- fluoro- using chloro-6-fluorobenzoyl)-O— benzoyl YOH piperidin-4-yloxy]phenyl}urea 491-(5-tert-Butyl-2-methyl-2H- Me 1,3- 2-Fluoro- 494.2 Ex. 2pyrazol-3-yl)-3-{3-[1-(2- phenyl- benzoyl usingfluorobenzoyl)-piperidin-4- O— YOH yloxy]phenyl}urea 501-(5-tert-Butyl-2-methyl-2H- Me 1,3- Benzoyl 476.2 Ex. 2pyrazol-3-yl)-3-{3-[1- phenyl- using benzoyl-piperidin-4- O— YOHyloxy]phenyl}urea 51 1-(5-tert-Butyl-2-methyl-2H- Me 1,3- 2-Trifluoro-544.2 Ex. 2 pyrazol-3-yl)-3-{3-[1-(2- phenyl- methyl- usingtrifluoromethyl O— benzoyl YOH benzoyl)-piperidin-4- yloxy]phenyl}urea52 1-(5-tert-Butyl-2-methyl-2H- Me 1,3- 2-Trifluoro- 560.2 Ex. 2pyrazol-3-yl)-3-{3-[1-(2- phenyl- methoxy- usingtrifluoromethoxybenzoyl)- O— benzoyl YOH piperidin-4-yloxy]phenyl}urea53 1-(5-tert-Butyl-2-methyl-2H- Me 1,3- 3-Pyrrolyl 465.2 Ex. 2pyrazol-3-yl)-3-{3-[1-(3- phenyl- carbonyl usingpyrrolyl)carbonyl-piperidin-4- O— YOH yloxy]phenyl}urea 541-(5-tert-Butyl-2-methyl- Me 1,3- Benzyloxy- 506.3 Ex. 3 using 4-(3-2H-pyrazol-3-yl)-3-{3-[1- phenyl- carbonyl Amino- (benzyloxy)carbonyl-O— phenoxy)- piperidin-4- piperidin-1-yl- yloxy]phenyl}urea carboxylicacid benzyl ester 55 1-(5-tert-Butyl-2H- H 1,4- 2,6- 530.0 Ex. 3 using3- pyrazol-3-yl)-3-{4-[1- phenyl- Dichloro- tert-Butyl-5-(2,6-dichlorobenzoyl)- O— benzoyl (222-trichloro- piperidin-4-ethoxy-carbonyl- yloxyl]phenyl}urea amino)-pyrazol- 1-yl-carboxylic acidtert-butyl ester 56 1-(5-tert-Butyl-2H- H 1,4- 2,6- 498.2 Ex. 55 using[4- pyrazol-3-yl)-3-{4-[1- phenyl- Difluoro- (4-amino-(2,6-difluorobenzoyl)- O— benzoyl phenoxy)- piperidin-4-piperidin-1-yl]- yloxy]phenyl}urea (2,6-difluoro- phenyl)- methanone 571-(5-tert-Butyl-2H- H 1,4- 2-Chloro- 496.1 Ex. 55 using [4-pyrazol-3-yl)-3-{4-[1-(2- phenyl- benzoyl (4-amino-chlorobenzoyl)-piperidin- O— phenoxy)- 4-yloxy]phenyl}ureapiperidin-1-yl]- (2-chloro- phenyl)- methanone 581-(5-tert-Butyl-2-methyl- Me 1,3- 2,6- 528.1 Ex. 3. using [4-2H-pyrazol-3-yl)-3-{3-[1- phenyl Dichloro- (3-Amino-(2,6-dichlorobenzoyl)- benzoyl phenyl)- piperidin-4- piperidin-1-yl]-yl]phenyl}urea (2,6-dichloro- phenyl)- methanone 591-(5-tert-Butyl-2-methyl- Me 2- 2-Chloro- 524.3 Ex. 3 using [4-2H-pyrazol-3-yl)-3-{3-[1- Methyl- benzoyl (5-amino-2-(2-chloro-benzoyl)- 1,5- methyl- piperidin-4-yloxy]-4- phenyl- phenoxy)-methyl-phenyl}-urea O— piperidin-1-yl]- (2-chloro- phenyl)- methanone 601-(5-tert-Butyl-2-methyl- Me 3- 2-Chloro- 578.2 Ex 28 using2H-pyrazol-3-yl)-3-{3-[1- trifluoro- benzoyl YOH. Starting(2-chlorobenzoyl)- methyl- with 1-(5-tert- piperidin-4-yloxy]-5- 1,5-Butyl-2-methyl- trifluoromethyl-phenyl}- phenyl- 2H-pyrazol-3- urea O—yl)-3-[3- (piperidin-4- yloxy)-5- trifluoromethyl- phenyl]-urea 611-(5-tert-Butyl-2-methyl- Me 3- 2,6- 580.2 Ex 60 using2H-pyrazol-3-yl)-3-{3-[1- trifluoro- Dichloro- YOH(2,6-difluoro-benzoyl)- methyl- benzoyl piperidin-4-yloxy]-5- 1,5-trifluoromethyl-phenyl}- phenyl- urea O— 621-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-(3-fluoro-5-{1-[4-(4-methyl-piperazin-1-ylmethyl)-benzoyl]-piperidin-4-yloxy}-phenyl)-ureaMe

4-(4-Methyl-piperazin-1-ylmethyl)-benzoyl 606.4 Ex 28usingYOH 631-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{1-[4-(2-(dimethylamino)-ethoxy)-benzoyl]-piperidin-4-yloxy}-5-fluoro-phenyl)-ureaMe

4-[2-(Dimethylamino)-ethoxy]-benzoyl 581.3 Ex 28.using4-[2-(Dimethylamino)-ethoxy]-benzoicacid 641-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indol-4-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-4-yl carbonyl 533.3 Ex 28usingYOH 651-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indol-5-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-5-yl carbonyl 533.3 Ex 28.usingYOH 661-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indol-7-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-7-yl carbonyl 533.3 Ex 28usingYOH 671-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indol-2-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-2-yl carbonyl 533.3 Ex 28usingYOH 681-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indole-3-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-3-yl carbonyl 533.3 Ex 28usingYOH 691-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1H-indol-6-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1H-Indol-6-yl carbonyl 533.3 Ex 28usingYOH 701-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(2,2-dimethyl-propionyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

2,2-Dimethyl-propionyl 474.3 Ex 28usingYOH 711-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[3-(1-cyclopropyl-piperidin-4-yloxy)-5-fluoro-phenyl]-ureaMe

Cyclopropylcarbonyl 458.2 Ex 28usingYOH 721-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(1-methyl-cyclopropylcarbonyl)-piperidin-4-yloxy]-phenyl}-ureaMe

1-Methyl-cyclopropylcarbonyl 472.3 Ex 28usingYOH 731-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(2,2-dichloro-cyclopropylcarbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

2,2-Dichloro-cyclopropylcarbonyl 526.2 Ex 28usingYOH 741-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(2,2-dichloro-1-methyl-cyclopropylcarbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

2,2-Dichloro-1-methyl-cyclopropylcarbonyl 540.2 Ex 28usingYOH 751-(5-tert-Butyl-2-methyl- Me 1,4- 3-Methyl- 496.3 Example 22H-pyrazol-3-yl)-3-{3-[1- phenyl- thien-2-yl using YOH(3-methyl-thiene-2-yl O— carbonyl carbonyl)-piperidin-4-yloxy]-phenyl}-urea 76 1-(5-tert-Butyl-2-methyl- Me 1,4- 3-Chloro- 516.2Example 2 2H-pyrazol-3-yl)-3-{3-[1- phenyl- thien-2- using YOH(3-chloro-thiene-2-ly O— ylcarbonyl carbonyl)-piperidin-4-yloxy]-phenyl}-urea 77 1-(5-tert-Butyl-2-methyl- Me 1,4- 1-(2,6- 537.3Example 2 2H-pyrazol-3-yl)-3-{3-[1- phenyl- Dimethoxy- using YOH(2,6-dimethoxy-pyridin-3- O— pyridin-3- yl carbonyl)-piperidin-4-yl)-carbonyl yloxy]-phenyl}-urea 78 1-(5-tert-Butyl-2-methyl- Me 1,4-1-(3,5- 545.3 Example 2 2H-pyrazol-3-yl)-3-{3-[1- phenyl- dichloro-using YOH (3,5-dichloro-pyridin-4-yl O— pyridin-4-ylcarbonyl)-piperidin-4- carbonyl yloxy]-phenyl}-urea 791-(5-tert-Butyl-2-methyl- Me 1,4- 2-Fluoro-6- 524.4 Example 22H-pyrazol-3-yl)-3-{3-[1- phenyl- methoxy- using YOH(2-fluoro-6-methoxy- O— benzoyl benzoyl)-piperidin-4-yloxy]-phenyl}-urea 80 1-(5-tert-Butyl-2-methyl- Me 1,4- 2,5- 494.4Example 2 2H-pyrazol-3-yl)-3-{3-[1- phenyl- Dimethyl- using YOH(2,5-dimethyl-1H-pyrrol-3- O— 1H-pyrrol- yl carbonyl)-piperidin-4- 3-ylyloxy]-phenyl}-urea carbonyl 81 1-(5-tert-Butyl-2-methyl- Me 1,4- 2,4-512.3 Example 2 2H-pyrazol-3-yl)-3-{3-[1- phenyl- Difluoro- using YOH(2,4-difluoro-benzoyl)- O— benzoyl piperidin-4-yloxy]- phenyl}-urea 821-(5-tert-Butyl-2-methyl- Me 1,4- 5-Chloro- 516.0 Example 22H-pyrazol-3-yl)-3-{3-[1- phenyl- thien-2-yl using YOH(5-chloro-thien-2-ly O— carbonyl carbonyl)-piperidin-4-yloxy]-phenyl}-urea 83 1-{3-[1-(5-Bromo-thien-2- Me 1,4- 5-Bromo- 562.0Example 2 yl carbonyl)-piperidin-2- phenyl- thien-2-yl using YOHyloxy]-phenyl}-3-(5-tert- O— carbonyl butyl-2-methyl-2H-pyrazol-3-yl)-urea 841-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(3-methyl-thien-2-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-urea Me

3-Methyl-thien-2-ylcarbonyl 514.3 Ex 28usingYOH 851-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(3-chloro-thien-2-carbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

3-Chloro-thien-2-ylcarbonyl 534.3 Ex 28usingYOH 861-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(2,6-dimethoxy-pyridine-3-carbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

1-(2,6-Dimethoxy-pyridin-3-yl)-carbonyl 555.4 Ex 28usingYOH 871-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(2-fluoro-6-methoxy-benzoyl)-piperidin-4-yloxy]-phenyl}-ureaMe

2-Fluoro-6-methoxy-benzoyl 542.4 Ex 28usingYOH 881-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(2,5-dimethyl-1H-pyrrol-3-ylcarbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-urea Me

2,5-Dimethyl-1H-pyrrol-3-ylcarbonyl 511.3 Ex 28using YOH 891-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-[1-(3,5-dichloro-pyridin-4-ylcarbonyl)-piperidin-4-yloxy]-5-fluoro-phenyl}-ureaMe

1-(3,5-Dichloro-pyridin-4-yl)-carbonyl 563.3 Ex 28 usingYOH 901-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(2-fluoro-benzoyl)-piperidin-4-yloxy]-phenyl}-ureap-tolyl

2-Fluoro-benzoyl 588.5 Ex 1 & 2-starting with3,5-difluoro-nitrobenzenein Prep 1, andstartingwith(5-tert-butyl-2-tolyl-2H-pyrazol-3-yl)-carbamicacid2,2,2-trichloro-ethylester inExample 1.Using YOH inExample 2 911-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[3-(1-cyclopropylcarbonyl-piperidin-4-yloxy)-5-fluoro-phenyl]-ureap-tolyl

Cyclopropylcarbonyl 534.5 Ex 1 & 2starting with3,5-difluoro-nitrobenzenein Prep 1, andstartingwith(5-tert-butyl-2-tolyl-2H-pyrazol-3-yl)-carbamicacid2,2,2-trichloro-ethylester inExample 1.Using YOH inExample 2 921-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(3-methyl-thien-2-ylcarbonyl)-piperidin-4-yloxy]-phenyl}-urea p-tolyl

3-Methyl-thien-2-ylcarbonyl 590.5 Ex 1 & 2startingwith3,5-difluoro-nitro benzenein Prep 1, andwith(5-tert-butyl-2-tolyl-2H-pyrazol-3-yl)-carbamicacid2,2,2-trichloro-ethylester inEx 1.Using YOH inEx 2

Example 931-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(3-morpholin-4-ylmethyl-benzoyl)-piperidin-4-yloxy]-phenyl}-urea

A mixture of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[3-formyl-benzoyl)-piperidin-4-yloxy]-phenyl}-urea(using Example 28, 103.9 mg, 0.2 mmol), morpholine (100 μL, 0.2 mmol),and sodium triacetoxyborohydride (96.1 mg, 0.45 mmol) in1,2-dichloroethane (2 mL) is stirred at 22° C. overnight. Solvent isevaporated and the residue is purified on silica gel with 0-5% (2 Mammonia in methanol) in dichloromethane to give a white solid (65.3 mg,55% yield, ES+(m/z) 593.3 [M+H]).

Example 944-{3-[3-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-ureido]-5-fluoro-phenoxy}-piperidine-1-carboxylicacid amide

Nitrogen gas is bubbled trough a solution of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea(390.6 mg, 1.0 mmol) and carbamic acid phenyl ester (140.6 mg, 1.0 mmol)in DMSO (2 mL) for 5 minutes. Next, N,N-diisopropylethylamine (350 μL,2.0 mmol) is added. After stirred at 85° C. overnight, the reactionmixture is distributed between ethyl acetate (15 mL) and saturatedsodium bicarbonate (50 mL). The aqueous phase is isolated and extractedwith ethyl acetate (2×15 mL). The combined organic phases are dried oversodium sulfate and concentrated. The residue is purified on a silica gelchromatography with hexanes and ethyl acetate to give a white solid (250mg, 58% yield, ES+(m/z) 433.3 [M+H]).

Example 951-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-[1-(2,2,2-trichloro-acetyl)-piperidin-4-yloxy]-phenyl}-urea

To an ice-water cooled solution of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea(390.6 mg, 1.0 mmol) and triethylamine (280 μL, mmol) in dichloromethane(5 mL) is added trichloroacetyl chloride (115 μL, 1.0 mmol). Thereaction mixture is allowed to warm up to 22° C. and stirred for 1 hour.After removal of solvent, the residue is purified on a silica gelchromatography with hexanes and ethyl acetate to provide a white solid(520.0 mg, 97% yield, ES+(m/z) 535.9 [M+H]).

Example 961-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(1-(4-methylsulfonyl-benzoyl)-piperidin-4-yl)-urea

Nitrogen gas is bubbled through a solution of(4-amino-piperidin-1-yl)-(4-methylsulfonyl-phenyl)-methanone (141.6 mg,0.50 mmol) and (5-tert-butyl-2-tolyl-2H-pyrazol-3-yl)-carbamic acid2,2,2-trichloro-ethyl ester (204.8 mg, 0.51 mmol) in DMSO (2 mL) for 2minutes. Next, N,N-diisopropylethylamine (0.20 mL) is added. Thereaction mixture is stirred at 60° C. for 6 hours. The crude product ispurified on a silica gel chromatography with ethyl acetate to give awhite solid (261.2 mg, 97.2%, ES+(m/z) 538.3 [M+H]).

Example 971-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-dichloro-benzoyl)-piperazin-1-ylmethyl]-phenyl}-urea

To a suspension of 75 mg (0.17 mmol) of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-ylmethyl-phenyl)-ureadihydrochloride in methylene chloride (4 mL) is added DIEA (0.103 mL,0.6 mmol) followed by 2,6-dichlorobenzoyl chloride (0.020 mL, 0.17mmol). The reaction mixture is stirred at room temperature overnight.Water is added (4 mL) and the organic layer separated, dried over sodiumsulfate, filtered and evaporated at reduced pressure to give a paleyellow oil. The residue is chromatographed using methylene chloride to92:8 methylene chloride:MeOH in a gradient. The title compound iscollected as a white solid (30 mg; 0.06 mmol, 33%). ES+(m/z) 544 [M+H].

Using essentially the methodology of Example 97 the following examplesare prepared:

ES+ Synthetic Ex m/z Method(s) No. Name R¹ Y [M + H] Analogous to: 981-(5-tert-Butyl-2-methyl- Me acetyl 413 Ex. 97 with2H-pyrazol-3-yl)-3-{4-[4- acetic acetyl-piperazin-1- anhydrideylmethyl]phenyl}urea 99 1-(5-tert-Butyl-2-methyl- Me 2-chloro- 509 Ex.97 with 2- 2H-pyrazol-3-yl)-3-{4-[4-(2- benzoyl chlorobenzoylchlorobenzoyl)-piperazin-1- chloride ylmethyl]phenyl}urea 1001-(5-tert-Butyl-2-methyl- Me 2,6- 511 Ex. 97 with2H-pyrazol-3-yl)-3-{4-[4- difluoro- 2,6-di- (2,6-difluorobenzoyl)-benzoyl fluorobenzoyl piperazin-1- chloride ylmethyl]phenyl}urea 1011-(5-tert-Butyl-2-methyl- Me 2,4- 511 Ex. 97 with2H-pyrazol-3-yl)-3-{4-[4- difluoro- 2,4-di- (2,4-difluoro-benzoyl)-benzoyl fluorobenzoyl piperazin-1-ylmethyl]- chloride phenyl}-urea 1021-(5-tert-Butyl-2-methyl- Me 2-chloro-4- 527 Ex. 97 with 2-2H-pyrazol-3-yl)-3-{4-[4-(2- fluoro- chloro-4- chloro-4-fluoro-benzoyl)-benzoyl fluorobenzoyl piperazin-1-ylmethyl]- chloride phenyl}-urea 1031-(5-tert-Butyl-2-methyl- Me 2-methoxy- 505 Ex. 97 with 2-2H-pyrazol-3-yl)-3-{4-[4-(2- benzoyl methoxybenzoyl methoxy-benzoyl)-chloride piperazin-1-ylmethyl]- phenyl}-urea 1041-[4-(4-Benzoyl-piperazin- Me benzoyl 475 Ex. 97 with1-ylmethyl)-phenyl]-3-(5- benzoyl tert-butyl-2-methyl-2H- chloridepyrazol-3-yl)-urea 105 1-(5-tert-Butyl-2-methyl Me 2-chloro-6- 528 Ex.97 with 2- 2H-pyrazol-3-yl)-3-{4-[4-(2- fluoro- chloro-6-fluorochloro-6-fluoro-benzoyl)- benzoyl benzoyl piperazin-l -ylmethyl]-chloride phenyl}-urea 106 1-(5-tert-Butyl-2-methyl- Me 2,4- 545 Ex. 97with 2H-pyrazol-3-yl)-3-{4-[4- dichloro 2,4-dichloro(2,4-dichloro-benzoyl)- benzoyl benzoyl piperazin-1-ylmethyl]- chloridephenyl}-urea 107 1-(5-tert-Butyl-2-methyl- Me 2,5- 551 Ex. 97 with2H-pyrazol-3-yl)-3-{4-[4- dichloro 2,5-dichloro (2,5-dichloro-thien-3-ylthienyl thienyl carbonyl)-piperazin-1- carbonyl carbonylylmethyl]-phenyl}-urea chloride 108 1-(5-tert-Butyl-2-methyl- Me4-trifluoro- 544 Ex. 97 with 4- 2H-pyrazol-3-yl)-3-{4-[4-(4- methyltrifluoro- trifluoromethyl-benzoyl)- benzoyl benzoylpiperazin-1-ylmethyl]- chloride phenyl}-urea 1091-(5-tert-Butyl-2-methyl- Me 4-fluoro 494 Ex. 97 with 4-2H-pyrazol-3-yl)-3-{4-[4-(4- benzoyl fluoro benzoylfluoro-benzoyl-piperazin-1- chloride ylmethyl]-phenyl}-urea 1101-(5-tert-Butyl-2-p-tolyl-2H- p-tolyl 2,6- 588 Ex. 97 withpyrazol-3-yl)-3-{4-[4-(2,6- difluoro- 2,6-di-fluorodifluoro-benzoyl)-piperazin- benzoyl benzoyl 1-ylmethyl]-phenyl}-ureachloride 111 1-(5-tert-Butyl-2-p-tolyl-2H- p-tolyl Cyclo- 516 Ex. 97with pyrazol-3-yl)-3-[4-(4- propane- cyclopropyl cyclopropylcarbonyl-carbonyl carbonyl piperazin-1-ylmethyl)- chloride phenyl]-urea 1121-[4-(4-Acetyl-piperazin-1- p-tolyl acetyl 490 Ex. 97 withylmethyl)-phenyl]-3-(5-tert acetic butyl-2-p-tolyl-2H-pyrazol- anhydride3-yl)-urea 113 1-(5-tert-Butyl-2-p-tolyl-2H- p-tolyl 2,6- 621 Ex. 97with pyrazol-3-yl)-3-{4-[4-(2,6- dichloro- 2,6-dichloro-dichloro-benzoyl)-piperazin- benzoyl benzoyl 1-ylmethyl]-phenyl}-ureachloride methylsulfonate 114 1-(5-tert-Butyl-2-ethyl-2H- Ethyl 2,6- 526Ex. 97 with pyrazol-3-yl)-3-{4-[4-(2,6- difluoro- 2,6-di-fluorodifluoro-benzoyl)-piperazin- benzoyl benzoyl 1-ylmethyl]-phenyl}-ureachloride 115 1-(5-tert-Butyl-2-isopropyl Isopropyl 2,6- 573 Ex. 97 with2H-pyrazol-3-yl)-3-{4-[4- dichloro- 2,6-dichloro-(2,6-dichloro-benzoyl)- benzoyl benzoyl piperazln-1-ylmethyl]- chloridephenyl}-urea 116 1-(5-tert-Butyl-2-isopropyl- Isopropyl 2,6- 540 Ex. 97with 2H-pyrazol-3-yl)-3-{4-[4- difluoro- 2,6-di-fluoro(2,6-difluoro-benzoyl)- benzoyl benzoyl piperazin-1-ylmethyl]- chloridephenyl}-urea

Using essentially the methodology of Example 97 the following examplesare prepared.

Synthetic ES+ Method(s) Ex m/z Analogous No. Name Y [M + H] to: 1171-(5-tert-Butyl-2-methyl-2H- 2,6- 544 Ex. 97 pyrazol-3-yl)-3-{3-[4-(2,6-dichloro- with 2,6- dichloro-benzoyl)-piperazin-1- benzoyl di-ylmethyl]-phenyl}-urea chloro- benzoyl chloride 1181-(5-tert-Butyl-2-methyl-2H- 2,6- 511 Ex. 97 pyrazol-3-yl)-3-{3-[4-(2,6-difluoro- with 2,6- difluoro-benzoyl)-piperazin-1- benzoyl di-ylmethyl]-phenyl}-urea benzoyl fluoro- chlorideUsing essentially the methodology of Example 97. The following examplesare prepared:

ES+ Synthetic Ex m/z Method(s) No. Name Y [M + H] Analogous to: 1191-(5-tert-Butyl-2-methyl-2H-pyrazol-3- 2,6- 531 Ex. 97 withyl)-3-{4-[4-(2,6-dichloro-benzoyl)- dichloro- 2,6-dipiperazin-1-yl]-phenyl}-urea benzoyl chlorobenzoyl chloride. 1201-(5-tert-Butyl-2-methyl-2H-pyrazol-3- 2,6- 498 Ex. 97 withyl)-3-{4-[4-(2,6-difluoro-benzoyl)- difluoro- 2,6-di-piperazin-1-yl]-phenyl}-urea benzoyl fluorobenzoyl chloride.

Example 1214-{4-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-phenyl}-piperazine-1-carboxylicacid amide

Using essentially the methodology of Example 97 but using trimethylsilylisocyanate instead of the acid chloride, the title compound is prepared.ES+(m/z) 476 [M+H]).

Using essentially the methodology of Example 97 but using thecorresponding sulfonyl chloride instead of the acid chloride, thefollowing compounds are prepared:

ES+ Synthetic m/z Method(s) Ex [M + Analogous No. Name Y H] to: 1221-(5-tert-Butyl-2-p-tolyl-2H- isopropyl- 539 Ex 97,pyrazol-3-yl)-3-{4-[4-(prop-2-yl sulfonyl withsulfonyl)-piperazin-1-yl]- isopropyl- phenyl}-urea sulfonyl chloride 1231-(5-tert-Butyl-2-p-tolyl-2H- cyclo- 537 Ex 97pyrazol-3-yl)-3-[4-(4-cyclopropyl- propyl- withsulfonyl-piperazin-1-yl)- sulfonyl cyclo- phenyl]-urea propyl sulfonylchloride

Example 1241-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-phenyl}-urea

The title compound is prepared by reaction of1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl-phenyl)-urea(0.20 g, 0.46 mmol) with 0.51 mmol of 3,3-Dimethyl-butyric acid, (0.06g, 0.46 mmol) of 1-Hydroxybenzotriazole hydrate and (0.8 g, 0.46 mmol)of polymer supported carbodiimide, dissolved in 16 mL of CH₂Cl₂. Mixtureis stirred at r.t.o.n. It is filtered and the resin is washed withCH₂Cl₂ Solvent is evaporated and the residue is purified with an SCXcartridge eluting with NH₄OH/CH₃OH 2 N. ES+(m/z) 531 [M+H].

Using essentially the methodology of Example 124 (reaction of1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-yl-phenyl)-ureawith the corresponding carboxylic acid) the following compounds areprepared. In the case of the piperidine-3-carboxylic acid, reaction iscarried out using the N-BOC derivative which is deprotected usingHCl/dioxane 4M.

ES+ m/z Ex [M + No. Name Y H] 1251-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3- Cyclopentyl- 543{4-[4-(2-cyclopentyl-acetyl)-piperazin-1- acetyl yl]-phenyl}-urea 1261-(5-tert-Butyl-2-p-tolyl-2H-pyrazol- Tetrahydro- 5313-yl)-3-{4-[4-(tetrahydro-fur-3-yl carbonyl)- fur-2-ylpiperazin-1-yl]-phenyl}-urea carbonyl 1271-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3- 1-Methyl- 515{4-[4-(1-methyl-cyclopropylcarbonyl)- cyclo-piperazin-1-yl]-phenyl}-urea propyl- carbonyl 1281-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3- 2-Methoxy- 519{4-[4-((R)-2-methoxy-propionyl)- propionyl piperazin-1-yl]-phenyl}-urea129 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- Cyclo- 5153-[4-(4-cyclobutylcarbonyl-piperazin-1-yl)- butyl- phenyl]-urea carbonyl130 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- 2,2- 5453-{4-[4-(2,2-dimethyl-pentanoyl)- Dimethyl- piperazin-1-yl]-phenyl}-ureapentanoyl 131 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- 2-Methyl- 5153-{4-[4-(2-methyl-cyclopropylcarbonyl)- cyclo-piperazin-1-yl]-phenyl}-urea propyl- carbonyl 1321-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- Piperidin-3- 5443-{4-[4-(piperidin-3-yl carbonyl)- yl carbonylpiperazin-1-yl]-phenyl}-urea

Example 1331-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-phenyl}-ureamethylsulfonate

0.11 mL of 1 N solution of methylsulfonic acid in CH₂Cl₂ is added to astirred solution of1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[4-(2,2-dimethyl-propionyl)-piperazin-1-yl]-phenyl}-ureain 1 mL of CH₂Cl₂, solution is stirred for 30 minutes. Salt solution isconcentrated in vacuo. Salt is crystallized by trituration with Et₂O.The solid is filtered and dried under vacuum to give the title compound.MS(ES+H): m/z=573

Using essentially the methodology of Example 133 the following examplesare prepared:

ES+ Ex m/z No. Name Y [M + H] 1341-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)- 2,6- 6063-{4-[4-(2,6-dichloro-benzoyl)- dichloro- piperazin-1-yl]-phenyl}-benzoyl urea methylsulfonate 135 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-Cyclo- 501 3-yl)-3-[4-(4-cyclopropylcarbonyl- propyl-piperazin-1-yl)-phenyl]-urea carbonyl methylsulfonate 1361-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3- tert-Butyl- 517yl)-3-{4-[4-(2,2-dimethyl-propionyl)- carbonylpiperazin-1-yl]-phenyl}-urea methylsulfonate 1371-(5-tert-Butyl-2-p-tolyl-2H-pyrazol- i-Butyl- 5033-yl)-3-[4-(4-isobutyryl-piperazin-1-yl)- carbonyl] phenyl]-ureamethylsulfonate

Example 1381-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(pyridin-4-ylcarbonyl)-piperazin-1-ylmethyl]-phenyl}-urea

To a suspension of 75 mg (0.17 mmol) of1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-piperazin-1-ylmethyl-phenyl)-ureadihydrochloride in methylene chloride (5 mL) is added DIEA (0.103 mL,0.6 mmol), PS-carbodiimide (266 mg, 0.34 mmol), HOBT (23 mg, 0.17 mmol)and then isonicotinic acid (21 mg, 0.17 mmol). The reaction mixture isshaken at room temperature overnight. Next, PS-trisamine (150 mg) isadded and the reaction mixture shaken at room temperature for 2 hr. Themixture is filtered and evaporated to afford a yellow oil, that ischromatographed using methylene chloride to 92:8 methylenechloride:methanol in a gradient. The title compound is collected as awhite solid weighing 12 mg (0.03 mmol, 18%). ES+(m/z)=476 [M+H]).

Using essentially the methodology of Example 138, the following exampleis prepared:

ES+ Synthetic m/z Method(s) Ex [M + Analogous No. Name Y H] to: 1391-(5-tert-Butyl-2-methyl-2H- 3-pyridinyl- 476 Ex. 138pyrazol-3-yl)-3-{4-[4-(pyridin-3- carbonyl with yl)carbonyl-piperazin-1-nicotinic ylmethyl]phenyl}urea acid

Using the method of Example 1. The following examples are prepared,wherein W′ contains one of the urea nitrogens:

ES+ Ex m/z No. Name R₁ W′ Y [M + H] 1401-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureaMe

2,6-difluoro-phenyl 530 1411-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(2,4-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureaMe

2,4-difluoro-phenyl 530 1421-(5-tert-Butyl-2-isopropyl-2H-pyrazol-3-yl)-3-{4-[4-(2,4-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureaIsopropyl

2,4-difluoro-phenyl 558 1431-(2,5-Di-tert-butyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureatert-Butyl

2,6-difluoro-phenyl 572 1441-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureaMe

2,6-difluoro-phenyl 530 1451-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[4-(2,4-difluoro-benzoyl)-piperazin-1-ylmethyl]-3-fluoro-phenyl}-ureaMe

2,4-difluoro-phenyl 530 1461-(5-tert-Butyl-2-ethyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-difluoro-benzoyl)-piperazin-1-ylmethyl]-2-fluoro-phenyl}-ureaEt

2,6-difluoro-phenyl 544 1471-(5-tert-Butyl-2-ethyl-2H-pyrazol-3-yl)-3-{4-[4-(2,4-difluoro-benzoyl)-piperazin-1-ylmethyl]-2-fluoro-phenyl}-ureaEt

2,4-difluoro-phenyl 544 1481-(5-tert-Butyl-2-ethyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-dichloro-benzoyl)-piperazin-1-ylmethyl]-2-fluoro-phenyl}-ureaEt

2,6-dichloro-phenyl 577 1491-(5-tert-Butyl-2-isopropyl-2H-pyrazol-3-yl)-3-{4-[4-(2,6-dichloro-benzoyl)-piperazin-1-ylmethyl]-2-fluoro-phenyl}-ureaIsopropyl

2,6-dichloro-phenyl 591

Example 1501-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(4-pyridin-4-ylmethyl-piperazin-1-ylcarbonyl)-phenyl]-urea

To a solution of4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid (0.08g, 0.26 mmol) in a mixture of dichloromethane (4 mL) and DMF (0.20 mL)is added 1-(4-pyridinylmethyl)piperazine (0.046 g, 0.26 mmol), PS-DCC(0.41 g, 0.52 mmol) and HOBT (0.035 g, 0.26 mmol). The mixture isstirred overnight at 45° C. in a closed tube (orbital stirring). ThenPS-Trisamine is added (0.52 mmol) and the mixture is stirred for 4 hr atroom temperature, filtrated, and washed three times withdichloromethane. The solvents are evaporated under reduced pressure andthe residue is purified by biotage column chromatography (eluent: ethylacetate/methanol 10:1) to give 0.020 g (0.04 mmol), 16% as white solid.ES+(m/z)=476 [M+H].

Inhibition of p38 Kinase Standard Solution Preparations

The kinase buffer solution is prepared by combining 2.5 mL 1M Tris-HCl(pH 7.5), 0.1 mL 1M dithiothreitol, 1.0 mL 1M magnesium chloride, and300 μL 1% Triton X-100 and diluting to 100 mL with water. 84 mL of thiskinase buffer solution is combined with 16 mL DMSO to prepare the 16%DMSO solution.

The 200 μM ATP solution is prepared by adding 102.6 μL 10 mM aqueousATP, 25 μL ³³P-ATP, and 163.5 μL of 4 mM aqueous Epidermal Growth FactorPeptide 661-681 (Biomol, Catalog #P-121) in 5 mL kinase buffer solution.

The p38 kinase enzyme solution is prepared by dissolving 9.5 μLconcentrated enzyme solution (250 ng p38 enzyme/μL kinase buffersolution) in 1536 μL kinase buffer solution.

Sample Preparation

An 80 μM solution of each test compound and control compound areprepared by dissolving 2 μL of a 10 mM stock solution of the respectivecompounds in dimethylsulfoxide in 248 μL of the 16% DMSO solution in aCostar 96-well microtiter plate. The plate is placed onto the TecanGenesis automated liquid handler for 1:3 serial dilutions.

Assay

10 μL of serially diluted compound is placed with a Beckman Multimek96-well automated liquid handler to the assay plate. 20 μL of 200 μM ATPsolution is added with a Titertek Multidrop 8-channel liquid handler. 10μL of p38 kinase enzyme solution is transferred to the assay plate usingthe Multimek. The mixture is allowed to react for 40 min at 30° C. andthen the reaction is stopped by adding 60 μL of freshly prepared 5%glacial AcOH with Multidrop. 80 μL of this solution is transferred to an“MAPH” plate using the Multimek. The plates are allowed to set for 30min at room temperature and then washed/aspirated on the Titertek MAPextractor with freshly prepared 0.5% glacial AcOH (1×300 μL, 2×200 μL).The wells are blotted and 100 μL MicroScint-20 scintillation fluid(Packard Bioscience) is added with the Multidrop. The plates are allowedto sit for 30 min and counted on a PE/Wallac Microbeta Triluxscintillation counter for ³³P-isotope.

All exemplified compounds are initially tested at 10 concentrations (20μM −1 nM using 1:3 serial dilutions). Compounds with IC₅₀ values lessthan 25 nM are re-tested at a starting concentration of 2 μM to 0.1 nM(1:3 serial dilutions). IC₅₀ values are calculated (IDBS ActivityBasesoftware) for each compound using non-linear regression. All exemplifiedcompounds were tested essentially as described above and were found toinhibit the p38 kinase enzyme with an IC₅₀ of less than 5 μM. Activityfor Examples 70, 100 and 136 in this assay was 0.019, 0.010 and 0.091μM, respectively.

Inhibition of TNF-α In Vitro Mouse Peritoneal Macrophages

1 mL thioglycolate broth (5.0 g yeast extract, 15.0 g casitone ortrypticase, 5.0 g dextrose, 2.5 g sodium chloride, 0.75 g L-cystine, 0.5g sodium thioglycolate, 1.0 mg resazurin, and 0.75 g agar in 1.0 Ldistilled water) are injected into the peritoneal cavity of Balb/Cfemale mice. At day 4 or 5 post-injection the mice are sacrificed andthen injected i.p. with 4 mL RPMI-1640 medium (BioWhittaker) and theperitoneal macrophages are withdrawn by syringe.

Cytokine Production

Mouse peritoneal microphages are counted with a hemocytometer andadjusted to 5×10⁵ cells/well in 96-well plates in RPMI-1640 medium with10% fetal bovine serum. 200 μL/well is plated in 96-well plates and thecells allowed to settle and adhere to the bottom of the well for atleast 3 hr. The test compound or standard p38 kinase inhibitor ispre-treated using a series of 8 concentrations for 1 hr at 37° C. (20μL/well). The cells are treated with a mixture of 50 ng/mLlipopolysaccharide (LPS) and 10 U/mL interferon-γ for 18 hr at 37° C.(20 μL/well). The conditioned media is harvested and assayed for TNF-αproduction using the Luminex procedure.

TNF-α/Luminex Detection Assay (Bio-Rad Bio-Plex Kit—Catalog #171-G12221)

The lyophilized premixed TNF-α standard (1 standard tube/two 96-wellplates) is reconstituted with 50 μL sterile water (500,000 pg/mL). Thesamples are vortexed for 5 seconds, incubated on ice for 30 min, andvortexed for 5 seconds before use. A set of twelve 1.5 mL tubes arelabeled with #1-thru #12 and then the amounts of cell media shown belowadded to the appropriate tubes (standard concentrations are as follows:50,000; 25,000; 12,500; 6,250; 3,125; 1,562.5; 781.3; 390.6; 195.3;97.7; 48.8; and 24.4 pg/mL). The premixed anti-cytokine conjugated beadsare vortexed (25×) vigorously for 30 seconds. The anti-cytokineconjugated beads are diluted to a 1× concentration using 1× Bio-PlexAssay Buffer. For every plate, 240 μL of the pre-mixed beads is added to5760 μL of Bio-Plex Assay Buffer. A Millipore 96-well filter plate isblocked with 100 μL/well of blocking buffer. The blocking buffer isfiltered through using a Millipore filtration system and then toweleddry. 2 washes are performed on the filter plate with 100 μL/well ofBio-Plex Assay Buffer and toweled dry. The 1× anti-cytokine conjugatedbeads are vortexed for 15 seconds and added 50 μL to each well. This isfiltered through and toweled dry. 2 washes are performed on plates with100 μl/well of Bio-Plex Wash Buffer. Again, it is filtered through andtoweled dry. 50 μL of sample or standard is added to each sample well.This is incubated for 60 seconds at room temperature on a shakerprotected from light at setting 6 and then for 30 min at setting 3 andthen placed in the refrigerator overnight. 3 washes are performed withBio-Plex Wash Buffer. Filter through and toweled dry. The cytokinedetection antibody is prepared (˜10 min prior to use) for every plateand 60 μL of the premixed cytokine detection antibody stock is added to5940 μL of Bio-Plex Detection Antibody Diluent.

50 μL of cytokine detection antibody is added and incubated for 60seconds at room temperature on a shaker protected from light at setting6 and then for 30 min at setting 3.3 washes are performed with theBio-Plex Wash Buffer. This is filtered through and toweled dry.Strept-PE (˜10 minutes prior to use) is prepared for every plate and 60μL to 5940 μL of Bio-Plex Assay Buffer added. 50 μL of Streptavidin-PEis added to each well and incubated for 60 seconds at room temperatureon a shaker protected from light at setting 6 and then for 10 min atsetting 3. 3 washes are performed with Bio-Plex Wash Buffer. This isfiltered through. The beads are re-suspended in 100 μL/well of Bio-PlexAssay Buffer. Standards and samples are read on a Luminex machine. Theseintensity readings are then converted to picogram/milliliter units basedon a 12-point standard curve created in duplicate using a four-parameterlogistic regression method (Bio-Plex Manager 2.0, Bio-Rad), and the IC₅₀calculated.

Representative members of the exemplified compounds were testedessentially as described above and suppressed TNF-α in vitro with anIC₅₀ less than 100 nM. Example 100 showed an IC50=11 nM in this assay.

Inhibition of TNF—In Vivo

Compounds are administered p.o. (30, 10, 3 and 1 mg/kg) to female Balb/cmice (6 mice/dose). 1 hr following compound administration at 4 doses(P.O. at volume of 0.1 mL/mouse; vehicle: 1% NaCMC/0.25% Tween-80 inwater); mice are given an IP-injection of LPS at 400 ug/kg. 1.5 hrsafter LPS challenging, mice are anesthetized with isoflurane and bloodis taken via cardiac puncture. TNFa-levels in the plasma are determinedusing ELISA kit from R&D Systems and dose response ED50 is determined.

Representative members of the exemplified compounds were testedessentially as described above and suppressed TNF—in vivo with an ED50less than 30 mg/kg. Example 100 showed a TMED50=2.4 mg/Kg in this assay.

Effect on Intra-Articular LPS Induced TNF-α

Intra-articular injection of LPS into rat ankles induces the synthesisof TNF-α, which can be measured in synovial lavage fluid. High levels ofTNF-α are detectable within 2 hours. Since the joint is the site wherearthritis develops, this model can rapidly determine whether an orallyadministered compound has an effect on an inflammatory response in thesynovium.

Six female Lewis rats (150-200 g) are place in each treatment group. Theanimals are given vehicle (1% NaCarboxymethylcellulose-0.25% Tween 80)or test compound (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg) orally. Onehour later, 10 μl LPS (10 μg) is administered intra-articularly into theright ankle of each rat, while the left ankle receives 10 μL of saline.After two hours, each ankle is lavaged with 100 μL of saline. The lavageis collected and stored at −80° C.

Group#1: Vehicle (1% NaCMC-0.25% Tween 80, 1 mL, PO)

Group#2: Test compound (1 mg/kg, 1 mL, PO)Group#3: Test compound (3 mg/kg, 1 mL, PO)Group#4: Test compound (10 mg/kg, 1 mL, PO)Group#5: Test compound (30 mg/kg, 1 mL, PO)

TNF-α is measured with a commercially available ELISA kit (R&D, RTA00).Treatment with Example 100 produced a dose response inhibition of TNF-αsynthesis, as measured in the synovial lavage fluid with ED50=30 mg/kg.

B16F10 Melanoma Target (MAPKAP-K2 Phosphorylation) and B16F10 MelanomaMetastasis Efficacy Model Inhibition of B16F10 Melanoma Lung Metastases

The B16F10 melanoma cell line is obtained from the American Type CultureCollection, Rockville, Md. The cells are cultured in RPMI-1640 mediumsupplemented with 10% fetal calf serum. The cells grown in vitro areharvested during their exponential growth phase by gentletrypsinization, washed twice in medium, and resuspended in serum-freeRPMI-1640 medium. The number of monodisperse viable cells is determinedusing a hemocytometer and adjusted to 1×10⁶ cells/mL. Tumor cells areinjected intravenously into the tail vein of normal C57B16 mice with aninoculum volume of 0.2 mL containing 200,000 cells. Mice are treatedwith test compound or vehicle control starting 1 day before i.v. tumorinoculation. The test compound is prepared as a suspension formulationin 1% NaCMC/0.25% polysorbate 80 and probe sonicated in an injectionvolume of 1% body weight (e.g., the 30 mg/kg dose level is prepared at 3mg/mL and 0.2 cc is administered per 20 g mouse). Mice are treatedorally tid. with the test compound at 30, 10, and 3 mg/kg (90, 30, and 9mg/kg/day) from days—1 thru 16 after tumor cell inoculation. Controlmice receive the vehicle alone in an identical manner. On day 16, themice are sacrificed, and the lungs are harvested and fixed in 3%paraformaldehyde. Lung lesions are quantitated by manual counting undera dissecting microscope.

B16F10 Target (Phosphorylated MAPKAPK-2) Studies

The B16F10 melanoma cell line is obtained from the American Type CultureCollection, Rockville, Md. The cells are cultured in RPMI-1640 mediumsupplemented with 10% fetal calf serum. The cells grown in vitro areharvested during their exponential growth phase by gentletrypsinization, washed twice in medium, and resuspended in serum-freeRPMI-1640 medium. The number of viable cells is determined using ahemocytometer and adjusted to 1×10⁷/mL. Tumor cells are injectedsubcutaneously in normal C57B16 mice. Inoculum volume per mouse is 0.2mL (2,000,000 cells). When the tumors reach 300-500 mg, the mice areused for target inhibition studies at either a fixed time (2.5 hours)after p.o. compound treatment or pharmacodynamic studies where thetumors are collected at multiple time-points (e.g., 3, 6, 9, 12, 15, and18 h) after p.o. compound treatment.

Protein Extraction and Immuno-Blot Analysis

Tumors collected as described above are immediately snap-frozen inliquid nitrogen and stored at −80° C. Tumor tissues are homogenized onice using a Daunce homogogenizer in an extraction buffer (25 mM Tris pH7.5 containing the following protease inhibitors: 10 μg/mL leupeptin, 10μg/mL soybean tryp-chymotrypsin inhibitor, 10 μg/mLN-tosyl-L-phenylalanine chloromethyl ketone, 10 μg/mL aprotinin,Nα-p-tosyl-L-arginine methyl ester, 7 mM benzamidine, 0.3 mMphenylmethylsulfonyl fluoride and two tablets of Roche complete proteaseinhibitor cocktail; following phosphatase inhibitors: 60 mMbeta-glycerophosphate, 1 mM sodium vanadate, 10 mM sodium fluoride. 20mM p-nitrophenyl phosphate, 1 μM okadaic acid, 1 μM microcystin, 2.5 mMsodium pyrophosphoate; and 1 mM dithiothreitol, 15 mM EDTA, 5 mM EGTA,1% Triton X100 and 150 mM NaCl). Tissue lysates are cleared bycentrifugation in a refrigerated microcentrifuge at 14,000 rpm and at 1°C. for 20 min. Supernatants are transferred to fresh microfuge tubesprechilled on ice and snap-freeze again in liquid nitrogen or dry ice.After quick thaw to about 80% completion in lukewarm water, the samplesare placed on ice to complete thaw. The samples are centrifuged again at14,000 rpm and at 1° C. for 15 min. The supernatant is transferred tofresh prechilled microfuge tubes and protein concentrations are measuredusing Bio-Rad protein assay reagents using bovine serum albumin asprotein standard.

Protein extracts are equalized with the extraction buffer. An equalvolume of 2×SDS sample buffer is added to the protein extracts andboiled in a waterbath for 5 min. 100 μg of protein extract per sample isused for electrophoresis on 4-20% gradient SDS-PAGE gel and transferredonto nitrocellulose (NC) membranes. NC membranes are blocked in 5% BSAin TBST (20 mM Tris pH=7.5, 500 mM NaCl, 0.05% Tween 20 and 0.02% sodiumazide) for at least 1 hr. The membranes are then incubated in primaryantibody at 1:1,000 with 5% BSA in TBST overnight on a shaker with 80rpm at 4° C. Membranes are washed 4×, 10 min each, with TBST. Themembranes are then incubated for 40 min with secondary antibody HRP(horse radish peroxidase) conjugate at 1:10,000 dilution in 3% non-fatmilk in TBST and washed again 4 times with TBST, 10 min each. Theimmuno-blots are then visualized by enhanced chemiluminescence (ECL,Amersham) as per manufacturer's instructions. All primary antibodies arepurchased from Cell Signaling and secondary antibody HRP conjugates areobtained from Amersham. Gels, membranes and apparatus used forelectrophoresis and Western blotting are purchased from Invitrogen.Protein bands of interest are quantified from films using Kodak ImageStation 1000.

P815 Tumor Model

Female (6-8 weeks old) DBA/2 mice (Taconic) are implanted subcutaneouslyinto the hind flank region on day 0 with P815 cells (0.5×10⁶ cells in200 ul of RPMI 1640). P815 tumor cells are purchased from ATCC and arecultured in RPMI 1640 medium, supplemented with glutamine and 10% bovineserum at 37° C. in 5% CO₂ cell culture incubator. Tumor-bearing animalsare treated with oral administration of test compound at different dosesor vehicle with frequency of three times a day started on the day ofimplantation. Tumor growth is monitored every 2 days by measuringperpendicular diameters. Tumor volume expressed in milligram (mg) isdetermined as the product of the largest diameter (a) and itsperpendicular (b) according to the formula [tumor volume=a×b²×0.536].

In Vivo Target Inhibition Study in P815 Mastocytoma Model

In vivo target inhibition is determined by measuring the effect ofinhibitor treatment on the phosphorylation of MAPKAP-K2 expressed, inP815 tumor tissues. Tumors in DBA/2 mice received P815 cellssubcutaneous implantation are allowed to grow to a size of 300-500 mgwithout treatment. Tumor bearing mice are then given oral administrationof test compound or vehicle. To investigate time course related targetinhibition by test compound, tumors are harvested from CO₂ sacrificedanimals at the indicated times (3 hr, 6 hr, 12 hr, and 18 hr) aftercompound is dosed at 30 mg/kg. Dose-dependent target inhibition by testcompound is investigated by harvesting tumors at 3 hr after orally givendifferent doses of test compound or vehicle. Harvested tumors areimmediately snap frozen onto dry ice, pulverized, homogenized and lysedin cooled lysis buffer containing proteinase and phosphatase inhibitors.After centrifugation to remove cell debris, supernatants containing 100microgram total proteins are resuspended in 2× Tris-Glycin loadingbuffer and subjected to sodium dodecyl sulfate-polyacrylamide gelelectrophoresis (10% Tris-Glycine) under reducing conditions. Proteinsare subsequently blotted onto a PDVF membrane and were then blocked in5% milk PBS containing 0.1% Tween-20 for 1 hr at room temperature. Themembrane is then incubated with primary antibody(anti-phospho-MAPKAP-K2, Cell Signaling) at 4° C. overnight followed byincubation with secondary antibody (anti-rabbit HRP-conjugated IgG) atroom temperature for 1 hr. Phospho-MAPKAP-K2 expression level isvisualized by Phospho-Image detection system after the enhancedchemiluminescence (ECL) detection is used to reflect the presence ofproteins on the PVDF blots. Expression level of phospho-p38 MAP kinaseand total p-38 MAP kinase is also monitored by similar western blottingprocedure.

Rat Collagen Induced Arthritis Efficacy Model

Female Lewis rats (≅190 g, Charles River Labs) are immunized with Bovinetype II collagen (2 mg/mL) emulsified with an equal volume of adjuvant(aluminum hydroxide). are used. The rats are immunized withapproximately 0.3 mg of the emulsion intradermally on the back near thebase of the tail. All animals are re-immunized 7 days later according tothe same protocol. The rats begin to develop arthritis (characterized byswelling and redness of one or both ankles) from 12 to 14 days after thefirst immunization. The rats are equally distributed into five treatmentgroups at the first signs of arthritis and treatment is initiated witheach rat dosed bid for 14 days.

Treatment Groups:

-   Group 1 Vehicle (1% NaCarboxymethylcellulose+0.25% Tween 80) 1 mL,    PO, Bid×14 days-   Group 2 Test compound, 5 mg/kg, 1 mL, PO, Bid×14-   Group 3 Test compound, 15 mg/kg, 1 mL, PO, Bid×14-   Group 4 Test compound, 30 mg/kg, 1 mL, PO, Bid×14 Group 5    Prednisolone 10 mg/kg, 1 mL, PO, qd×14    Ankle diameter is measured with calipers 5 days a week and recorded.    Data is expressed as the area under the curve (AUC) generated from    the composite inflammation scores and statistical analysis    performed.

Oral administration of the compounds of the present invention ispreferred. However, oral administration is not the only route or eventhe only preferred route. For example, transdermal administration may bevery desirable for patients who are forgetful or petulant about takingoral medicine, and the intravenous route may be preferred as a matter ofconvenience or to avoid potential complications related to oraladministration. Compounds of Formula I may also be administered by thepercutaneous, intramuscular, intranasal or intrarectal route inparticular circumstances. The route of administration may be varied inany way, limited by the physical properties of the drugs, theconvenience of the patient and the caregiver, and other relevantcircumstances (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)).

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material that can serve as a vehicle or medium forthe active ingredient. Suitable carriers or excipients are well known inthe art. The pharmaceutical composition may be adapted for oral,inhalation, parenteral, or topical use and may be administered to thepatient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations of the present invention may bedetermined by methods well known to the skilled artisan.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as povidone,hydroxypropyl cellulose, microcrystalline cellulose, or gelatin;excipients or diluents such as: starch, lactose, microcrystallinecellulose or dicalcium phosphate, disintegrating agents such as:croscarmellose, crospovidone, sodium starch glycolate, corn starch andthe like; lubricants such as: magnesium stearate, stearic acid, talc orhydrogenated vegetable oil; glidants such as colloidal silicon dioxide;wetting agents such as: sodium lauryl sulfate and polysorbate 80; andsweetening agents such as: sucrose, aspartame or saccharin may be addedor a flavoring agent such as: peppermint, methyl salicylate or orangeflavoring. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such aspolyethylene glycol or a fatty oil. Other dosage unit forms may containother various materials that modify the physical form of the dosageunit, for example, as coatings. Thus, tablets or pills may be coatedwith sugar, hydroxypropyl methylcellulose, polymethacrylates, or othercoating agents. Syrups may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

The compounds of Formula I are generally effective over a wide dosagerange.

For example, dosages per day normally fall within the range of about0.0001 to about 30 mg/kg of body weight. In some instances dosage levelsbelow the lower limit of the aforesaid range may be more than adequate,while in other cases still larger doses may be employed without causingany harmful side effect, and therefore the above dosage range is notintended to limit the scope of the invention in any way. It will beunderstood that the amount of the compound actually administered will bedetermined by a physician, in the light of the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound or compounds administered, the age,weight, and response of the individual patient, and the severity of thepatient's symptoms.

1. A compound of Formula I:

wherein: R¹ is hydrogen, C₁-C₄ alkyl, or tolyl; W is1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C₁-C₂ alkoxy)-naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,(1-Y-piperidin-4-yloxy)-phenyl-,[1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-,(1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenylis optionally substituted with one to two substituents from the groupconsisting of halo, methyl, and trifluoromethyl; Y is —C(O)—R², C₁-C₃alkylsulfonyl, or cyclopropylsulfonyl; and R² is C₁-C₆ alkyl, C₁-C₆alkoxy-(C₁-C₆ alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl,piperidinyl, trichloromethyl, cyclopentylmethyl; C₃-C₅ cycloalkyloptionally substituted with 1-3 substituents independently selected fromthe group consisting of phenyl, C₁-C₄ alkyl, and halo, pyridinyloptionally substituted with 1-2 substituents independently selected fromthe group consisting of C₁-C₄ alkoxy and halo, thienyl optionallysubstituted with 1-2 halo or C₁-C₄ alkyl substituents, pyrrolyloptionally substituted with 1-2 C₁-C₄ alkyl substituents, imidazolyl,pyrazolyl optionally substituted with 1-3 C₁-C₄ alkyl substituents, orphenyl substituted with 1-2 substituents independently selected from thegroup consisting of halo, trifluoromethyl, trifluoromethoxy, C₁-C₄alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein W is 1-(2,6-dichlorobenzoyl)-piperidin-4-yl-phenyl-,(1-Y-piperazin-4-yl)-phenyl-, or (1-Y-piperidin-4-yloxy)-phenyl-.
 3. Acompound according to claim 1 wherein R¹ is methyl.
 4. A compoundaccording to claim 1 wherein R¹ is tolyl.
 5. A compound according toclaim 1 wherein Y is C(O)—R².
 6. A compound according to claim 1 whereinR² is phenyl substituted 1-2 times with halo.
 7. (canceled)
 8. Acompound according to claim 1 wherein R² is cyclopropyl.
 9. Apharmaceutical formulation comprising a compound of Formula I:

wherein: R¹ is hydrogen, C₁-C₄ alkyl, or tolyl; W is1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C₁-C₂ alkoxy)-naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,(1-Y-piperidin-4-yloxy)-phenyl-,[1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-,(1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenylis optionally substituted with one to two substituents from the groupconsisting of halo, methyl, and trifluoromethyl; Y is —C(O)—R², C₁-C₃alkylsulfonyl, or cyclopropylsulfonyl; and R² is C₁-C₆ alkyl, C₁-C₆alkoxy-(C₁-C₆ alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl,piperidinyl, trichloromethyl, cyclopentylmethyl; C₃-C₅ cycloalkyloptionally substituted with 1-3 substituents independently selected fromthe group consisting of phenyl, C₁-C₄ alkyl, and halo, pyridinyloptionally substituted with 1-2 substituents independently selected fromthe group consisting of C₁-C₄ alkoxy and halo, thienyl optionallysubstituted with 1-2 halo or C₁-C₄ alkyl substituents, pyrrolyloptionally substituted with 1-2 C₁-C₄ alkyl substituents, imidazolyl,pyrazolyl optionally substituted with 1-3 C₁-C₄ alkyl substituents, orphenyl substituted with 1-2 substituents independently selected from thegroup consisting of halo, trifluoromethyl, trifluoromethoxy, C₁-C₄alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl; or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, excipient, or carrier.
 10. A method of inhibitingp-38 kinase in a mammal comprising administering to a mammal in need ofsuch treatment an effective amount of a compound of Formula I:

wherein: R¹ is hydrogen, C₁-C₄ alkyl, or tolyl; W is1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C₁-C₂ alkoxy)-naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,(1-Y-piperidin-4-yloxy)-phenyl-,[1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-,(1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenylis optionally substituted with one to two substituents from the groupconsisting of halo, methyl, and trifluoromethyl; Y is —C(O)—R², C₁-C₃alkylsulfonyl, or cyclopropylsulfonyl; and R² is C₁-C₆ alkyl, C₁-C₆alkoxy-(C₁-C₆ alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl,piperidinyl, trichloromethyl, cyclopentylmethyl; C₃-C₅ cycloalkyloptionally substituted with 1-3 substituents independently selected fromthe group consisting of phenyl, C₁-C₄ alkyl, and halo, pyridinyloptionally substituted with 1-2 substituents independently selected fromthe group consisting of C₁-C₄ alkoxy and halo, thienyl optionallysubstituted with 1-2 halo or C₁-C₄ alkyl substituents, pyrrolyloptionally substituted with 1-2 C₁-C₄ alkyl substituents, imidazolyl,pyrazolyl optionally substituted with 1-3 C₁-C₄ alkyl substituents, orphenyl substituted with 1-2 substituents independently selected from thegroup consisting of halo, trifluoromethyl, trifluoromethoxy, C₁-C₄alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl; or apharmaceutically acceptable salt thereof.
 11. A method of treatingconditions resulting from excessive cytokine production in a mammalcomprising administering to a mammal in need of such treatment acytokine-suppressing amount of a compound of Formula I:

wherein: R¹ is hydrogen, C₁-C₄ alkyl, or tolyl; W is1-(4-methylsulfonylbenzoyl)-piperidin-4-yl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yloxy]naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-(C₁-C₂ alkoxy)-naphthyl-,[1-(2,6-dichlorobenzoyl)-piperidin-4-yl]-phenyl-,(1-Y-piperidin-4-yloxy)-phenyl-,[1-(2,6-dichlorobenzoyl)-piperazin-4-yl]-methyl-phenyl-,(1-Y-piperazin-4-yl)-methyl-phenyl-, (1-Y-piperazin-4-yl)-phenyl-, or4-[1-(pyridin-4-ylmethyl)-piperazin-4-ylcarbonyl]-phenyl- wherein phenylis optionally substituted with one to two substituents from the groupconsisting of halo, methyl, and trifluoromethyl; Y is —C(O)—R², C₁-C₃alkylsulfonyl, or cyclopropylsulfonyl; and R² is C₁-C₆ alkyl, C₁-C₆alkoxy-(C₁-C₆ alkyl), amino, benzyloxy, indolyl, tetrahydrofuryl,piperidinyl, trichloromethyl, cyclopentylmethyl; C₃-C₅ cycloalkyloptionally substituted with 1-3 substituents independently selected fromthe group consisting of phenyl, C₁-C₄ alkyl, and halo, pyridinyloptionally substituted with 1-2 substituents independently selected fromthe group consisting of C₁-C₄ alkoxy and halo, thienyl optionallysubstituted with 1-2 halo or C₁-C₄ alkyl substituents, pyrrolyloptionally substituted with 1-2 C₁-C₄ alkyl substituents, imidazolyl,pyrazolyl optionally substituted with 1-3 C₁-C₄ alkyl substituents, orphenyl substituted with 1-2 substituents independently selected from thegroup consisting of halo, trifluoromethyl, trifluoromethoxy, C₁-C₄alkoxy, 2-(dimethylamino)ethoxy, and morpholin-4-ylmethyl; or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, excipient, or carrier.
 12. The method of claim 11,where the cytokine is tumor necrosis factor α.